Compounds and methods for modulating fxr

ABSTRACT

Compounds of formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.

FIELD OF THE INVENTION

The current invention relates to the fields of medicinal organicchemistry, pharmacology, and medicine. Specifically, the inventionrelates to novel compounds useful for the treatment of diseases relatedto dyslipidemia.

BACKGROUND OF THE INVENTION

Dyslipidemia and diseases related to dyslipidemia e.g. atherosclerosis,coronary artery disease, stroke, etc., are major causes of death,morbidity, and economic loss. Plasma lipids, especially cholesterolfractions, are recognized as having a significant role in cardiovascularhealth. Favorable modulation of plasma lipid such as triglycerides, HDLcholesterol, and LDL cholesterol is desirable.

Numerous efforts are underway to provide safe and efficacious molecularentities for the treatment of diseases related to dyslipidemia. Forexample, International application WO 2004/048349 A1 discloses compoundsuseful as farnesoid X receptor (FXR) agonists.

FXR agonists are ligands for a nuclear receptor that regulates thetranscription of genes that control triglyceride, cholesterol, andcarbohydrate metabolism. The above efforts and others not withstanding,there remains a need to discover and develop compounds that are believedto be (1) potent, (2) efficacious (based on in-vivo models) and/or (3)selective agonists of FXR. Such compounds would be useful for treatmentof disorders characterized by or resulting from an undesirable lipidprofile including dyslipidemia, atherosclerosis, diabetes and relateddiseases.

The present invention provides compounds that that are believed to be(1) potent, (2) efficacious (based on in-vivo models) and/or (3)selective agonists of the FXR.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula

whereinp is 0, 1 or 2;X₁ is C or N and X₂ is C or N; provided that both X₁ and X₂ are not N;R¹ and R² are independently selected from the group consisting ofhydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ thiohaloalkyl, C₁-C₃alkoxy, C₁-C₃ haloalkoxy, and halo;R³ is independently selected from the group consisting of hydrogen,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, and halo;R^(4b) is selected from the group consisting of hydrogen, C₁-C₃ alkyl,C₁-C₃ haloalkyl, C₃-C₆ cycloalkyl, and C₄-C₅ alkylcycloalkyl;R⁵ and R^(5a) are independently selected from the group consisting ofhydrogen, and C₁-C₃ alkyl;R⁶ is selected from the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, halo, and —NO₂;L₁ is selected from the group consisting of a bond, CR^(a)═CR^(b),ethynyl, C₁-C₃ alkyl-S—, C₁-C₃ alkyl-O—, N(R^(c))—C₁-C₃ alkyl, and—C₁-C₃ alkyl-N(R^(c))—, wherein R^(a) and R^(b) are independentlyselected from the group consisting of hydrogen and C₁-C₃ alkyl; andR^(c) is independently selected from the group consisting of H, C₁-C₅alkyl, C₁-C₃ alkylphenyl, and C₄-C₈ alkylcycloalkyl;Ar¹ is selected from the group consisting of indolyl, benzothienyl,benzoisothiazolyl, indazolyl, naphthyl, phenyl, pyridinyl, pyrazolyl,pyrrolyl, thienyl, thiazolyl, and furanyl, each optionally substitutedwith one or two groups independently selected from the group consistingof hydroxy, C₁-C₃ alkyl, C₁-C₃ haloalkyl, halo, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ alkoxy, —OC₁-C₂ alkylphenyl, and NHC(O)R¹⁰;R⁷ is selected from the group consisting of —COOH, —C₁-C₃ alkylCOOH,—O—C₁-C₃ alkylCOOH, —C₃-C₈ cycloalkylCOOH and, —CONR¹¹R¹¹;each R¹⁰ is independently selected from the group consisting ofhydrogen, C₁-C₃ alkyl, and phenyl;each R¹¹ is independently hydrogen, or C₁-C₅ alkyl; or apharmaceutically acceptable salt thereof.

The compounds of present invention are agonists of FXRs. The compoundsof present invention are useful for beneficially altering lipidprofiles, including but not limited to lowering total cholesterol,lowering LDL cholesterol, lowering VLDL cholesterol levels, raising HDLlevels, lowering triglyceride levels and beneficially sensitizingproduction of insulin in response to glucose levels. Thus the presentinvention provides a method for treating FXR mediated conditions such asdyslipidemia and diseases related to dyslipidemia comprisingadministering a therapeutically effective amount of a compound ofpresent invention to a patient in need thereof.

The present invention also provides a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to the use of a compound of thepresent invention for the manufacture of a medicament.

DETAILED DESCRIPTION OF THE INVENTION

The term “dyslipidemia” as used herein refers to abnormality in, orabnormal amounts of lipids and lipoproteins in the blood and the diseasestates resulting, caused by, exacerbated by or adjunct to suchabnormality (see Dorland's Illustrated Medical Dictionary, 29th edition,W.B Saunders publishing Company, New York, N.Y.). Disease statesencompassed within the definition of dyslipidemia as used herein includehyperlipidemia, hypertriglyceremia, low plasma HDL, high plasma LDL,high plasmaVLDL, liver cholestasis, and hypercholesterolemia.

The phrase “diseases related to dyslipidemia” as used herein refers todiseases including but not limited to atherosclerosis, thrombosis,coronary artery disease, stroke, and hypertension. Diseases related todyslipidemia also include metabolic diseases such as obesity, diabetes,insulin resistance, and complications thereof. Complications of diabetesinclude but are not limited diabetic retinopathy.

As used herein, the term “patient” refers to humans, companion animals(e.g. dogs and cats and the like), and livestock animals.

The terms “treatment” “treat” and “treating” include ameliorating,halting, restraining, slowing, and reversing the progression of, orreducing the severity of pathological symptoms of dyslipidemia anddiseases related to dyslipidemia.

As used herein, the term “therapeutically effective amount” means anamount of a compound of the invention that is part of an approvedtherapeutic regimen, or is determined by a qualified prescriber to besufficient taken as directed, for treating a condition, or detrimentaleffects thereof herein described.

The term “pharmaceutically acceptable” is used herein as an adjectiveand means substantially non-deleterious to the recipient patient.

The term “C₁-C₃ alkyl” represents a straight or branched hydrocarbonmoiety having from 1 to 3 carbon atoms, including methyl, ethyl,n-propyl, and isopropyl. It is understood by one of skill in the artthat a “C₁-C₃ alkyl” is synonymous with a “C₁-C₃ alkylene” a diradicalwhen the “C₁-C₃ alkyl” group is sandwiched between two groups such thatit is becomes a diradical. Similarly, the terms “C₁-C₄ alkyl” or “C₁-C₅alkyl” or “C₁-C₆” refer to straight or branched chain alkyl group having1 to 4 or 1 to 5 or 1 to 6 carbon atoms respectively.

The term “C₂-C₄ alkenyl” or the like represents a straight or branchedhydrocarbon moiety having at least one double bond and having from 2 to4 carbon atoms. Examples include but are not limited to vinyl, propenyl,2-butenyl.

The term “C₂-C₄ alkynyl” or the like represents a straight or branchedhydrocarbon moiety having at least one triple bond and having from 2 to4 carbon atoms. Examples include but are not limited to vinyl, propynyl,2-butynyl, and the like.

The term “C₃-C₆ cycloalkyl” refers to a saturated carbocyclic ringhaving from 3 to 6 carbon atoms (or as indicated), including but notlimited to cyclopropyl, cyclopentyl and cyclohexyl. Similarly, the term“C₃-C₈ cycloalkyl” refers to a saturated carbocyclic ring having from 3to 8 carbon atoms including but not limited to cyclopropyl, cyclopentyland cyclohexyl.

The term “C₄-C₅ alkylcycloalkyl” as used herein refers to thecombination of an alkyl and a cycloalkyl group such that the totalnumber of carbon atoms is 4 to 5. For example, C₄-C₅ alkylcycloalkylincludes —CH₂Cyclopropyl, i.e. methylcyclopropyl which isC₄alkylcycloalkyl.

The term “halo” means halogens including iodo, chloro, bromo and fluoro.

The term “C₁-C₃ haloalkyl” refers to a C₁-C₃ alkyl (or as indicated)group substituted with one, two, three or more halogen atoms asindicated or chemically appropriate. Examples of C₁-C₃ haloalkyl includebut are not limited to trifluoromethyl, chloroethyl, and 2-chloropropyl.

A “C₁-C₃ alkoxy” group is a C₁-C₃ alkyl moiety connected through an oxylinkage. Examples of alkoxy groups include but are not limited tomethoxy (-OMe (OCH₃)), ethoxy (-OEt (—OCH₂CH₂)), propoxy (-OPr(—OCH₂CH₂CH₂)), isopropoxy (-OiPr (—OCHCH₃CH₃)), etc.

The term “—C₁-C₃ alkyl-O—” referred to as alkyloxy represents an alkylgroup (C₁-C₅ alkyl or as indicated) terminating in an oxygen atom asdistinct from alkoxy (—O—C₁-C₅ alkyl) reading from left to right. Forexample radicals or groups such as —CH₂O—, —CH₂CH₂O—, and —CH(CH₃)O— areherein classified as alkyloxy groups.

The term “C₁-C₃ haloalkoxy” refers to a C₁-C₃ alkoxy wherein one or moreof the hydrogen atoms on the alkyl portion have been replaced withhalogens. Examples of C₁-C₃ haloalkoxy groups include difluoromethoxy,trifluoromethoxy, 2-haloethoxy, 2,2,2-trifluoroethoxy, up to andincluding like groups having the indicated number of carbon atoms.

It is understood that when Ar¹ is bicyclic, attachment of Ar¹ to thering containing R⁶ can occur at any carbon atom of the bicyclic ringunless otherwise indicated.

A compound of the invention may occur as any one of its isomers all ofwhich are objects of the invention. Certain compounds of the inventionmay possess one or more chiral centers, and thus, may exist in opticallyactive forms. Likewise, compounds of the invention may have alkenylgroups, and thus, may exist as geometric isomers. All such isomers aswell as the mixtures thereof are within the ambit of the presentinvention. If a particular stereoisomer is desired, it can be preparedby methods well known in the art.

PREFERRED EMBODIMENTS OF THE INVENTION

Preferably X₁ and X₂ are both C. Also preferred is a compound of theinvention wherein X₁ is N.

Preferably p is 0, or 1. More preferably, p is 0.

Preferably R¹ and R² group are each independently selected from thegroup consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃alkoxy, C₁-C₃ haloalkoxy, —SC₁-C₃ alkyl, —SC₁-C₃ haloalkyl, and halo.More preferably, R¹ and R² groups are independently selected from thegroup consisting of hydrogen, chloro, fluoro, CF₃, OCF₃, and SCF₃.

A preferred R³ group is selected from the group consisting of hydrogen,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, and halo.More preferred is an R³ group selected from the group consisting ofhydrogen, chloro, fluoro, CF₃, OCF₃, and SCF₃. Most preferably, R³ ishydrogen or absent.

Preferably, R^(4b) is independently selected from H, methyl, ethyl,propyl, isopropyl, cyclopropyl, CF₃, and methylcyclopropyl. Morepreferably, R^(4b) is CF₃, isopropyl or cyclopropyl.

Preferably, R⁵ and R^(5a) are each independently selected from the groupconsisting of hydrogen, methyl and ethyl. More preferably, R⁵ and R^(5a)are both hydrogen.

A preferred R⁶ group is selected from the group consisting of hydrogen,halo, C₁-C₃ alkyl, C₂-C₃ alkenyl, hydroxy, —NO₂, and —OC₁-C₂ alkyl. Morepreferably, R⁶ is selected from the group consisting of hydrogen, halo,methyl, and methoxy. Most preferably, R⁶ is hydrogen, chloro, or methyl.

Preferred L₁

L₁ is preferably selected from the group consisting of a bond, CH═CH,ethynyl, —CH₂S—, —C(CH₃)₂—S—, —CH(CH₂CH₃)S—, —CH(CH₃)S—, —CH(CH₃)CH₂—S—,—CH(CH₃)CH₂O—, —C(CH₃)₂O—, —CH(CH₃)O—, —CH(CH₂CH₃)O—,—N(R^(c))(CH₂)_(m)—, and —(CH₂)_(m)—N(R^(c))— wherein R^(c) is hydrogenor C₁-C₃ alkyl, m is 1, 2, or 3. More preferably, L₁ is a bond, CH═CH,—N(CH₃)CH₂,

—N(CH₃)CH₂CH₂, or —N(CH₃)CH₂CH₂CH₂—. More particularly preferred L₁ is abond, —N(CH₃)CH₂, or —N(CH₃)CH₂. Most preferably L₁ is —N(CH₃)CH₂, or—N(CH₃)CH₂CH₂.

A preferred Ar¹ group is selected from the group consisting ofoptionally substituted indolyl, indazolyl, thienyl, benzothienyl,benzisothiazolyl, phenyl, pyridinyl, pyrrolyl, thiazolyl, and furanyl.More preferably, Ar¹ is selected from the group consisting of optionallysubstituted benzothienyl, indolyl, indazolyl, benzoisothiazolyl, andphenyl. A particularly preferred Ar¹ is phenyl, indolyl, benzothienyl,or benzoisothiazolyl. Preferably Ar¹ is optionally substituted with oneor two groups independently selected from the group consisting of halo,C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, and C₁-C₃ haloalkyl.

A preferred R⁷ substituent is COOH or CONHR¹¹. More preferably, R⁷ isCOOH or CONH₂, —CONHCH₃, or CONHC₂H₅. Most preferably R⁷ is COOH.

R¹⁰ is preferably hydrogen, or C₁-C₃ alkyl.

R¹¹ is preferably C₁-C₃ alkyl.

Also preferred is a compound of the invention wherein:

p is 0 or 1;X₁ and X₂ are both C, or X₁ is N and X₂ is C;R¹ and R² are independently selected from the group consisting ofhydrogen, fluoro, chloro, CF₃, SCF₃, OCF₃,R³ is hydrogen, fluoro, chloro C₁-C₃ alkyl, CF₃, SCF₃, or OCF₃;R^(4b) is H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, or C₃-C₄cycloalkyl;R⁵ and R^(5a) are each independently selected from H or C₁-C₃ alkyl;Ar¹ group is phenyl, indolyl, pyridinyl, pyrrolyl, thienyl, naphthyl,thiazolyl, furanyl, pyrazolyl, indazolyl, benzoisothiazolyl, andbenzothienyl each optionally substituted with one to two groupsindependently selected from C₁-C₅ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkoxy,and C₁-C₃ haloalkyl;R⁶ is hydrogen, methyl, ethyl or chloro;L₁ is a bond, ethenyl, —CH(CH₃)—S—, C(CH₃)₂—S—, —CH₂O—, —CH₂CH₂O—,—CH(CH₃)—O—, —CH(CH₃)CH₂—O—, —CH(CH₂CH₃)—O—, —CH₂NH—, —CH₂CH₂NH—,—N(R^(c))CH₂—, N(R^(c))CH₂CH₂—, or N(R^(c))CH₂CH₂CH₂—; wherein R^(c) ishydrogen, C₁-C₂ alkyl, benzyl or —CH₂CH₂—O—CH₂—;R⁷ is COOH, —CH₂COOH, —CH(CH₃)COOH, -cyclopropylCOOH, —C(CH₃)₂COOH,CONH₂, C(O)NHCH₃, or C(O)NHCH₂CH₃;R¹⁰ is hydrogen or C₁-C₂ alkyl; andR¹¹ is hydrogen or C₁-C₂ alkyl.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; R⁵ and R^(5a) are both hydrogen; L₁ is ethenyl,acetylene, —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁶ is hydrogen, methyl,chloro or bromo; Ar¹ is phenyl, indolyl, indazolyl, benzothienyl, orbenzoisothiazolyl, each optionally substituted with a group selectedfrom methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,isopropoxy and cyclopropoxy; and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ and R^(5a) areboth hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹ is phenyl,benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionallysubstituted with a group selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is —N(CH₃)CH₂—, or—N(CH₃)CH₂CH₂—; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl,ethyl or chloro; Ar¹ is phenyl, optionally substituted with a groupindependently selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is a bond, —N(CH₃)CH₂—, or—N(CH₃)CH₂CH₂—; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl,ethyl or chloro; Ar¹ is phenyl, benzoisothiazolyl, indazolyl, indolyl orbenzothienyl, each optionally substituted with a group selected frommethyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy,isopropoxy and cyclopropoxy; and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is ethenyl, —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ andR^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionallysubstituted with a group selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is a bond, —CH(CH₃)O,—CH(CH₃)CH₂O, —CH(CH₃)S, —C(CH₃)₂S, —CH₂—NH—, and —CH₂N(CH₃)—; R⁵ andR^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, eachoptionally substituted with a group selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy;and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 0; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is ethenyl, —CH(CH₃)O, —CH(CH₃)CH₂O, —CH(CH₃)S,—C(CH₃)₂S, —CH₂—NH—, and —CH₂N(CH₃)—; R⁵ and R^(5a) are both hydrogen;R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl orchloro; Ar¹ is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, eachoptionally substituted with a group selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy;and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 1; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is —N(CH₃)CH₂—, or—N(CH₃)CH₂CH₂—; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl,ethyl or chloro; Ar¹ is benzoisothiazolyl, indazolyl, indolyl orbenzothienyl, each optionally substituted with a group independentlyselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,ethoxy, isopropoxy and cyclopropoxy; and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 1; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is a bond; R⁵ and R^(5a)are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹ isphenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, eachoptionally substituted with a group independently selected from methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 1; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is a bond; R⁵ and R^(5a)are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹ isphenyl optionally substituted with a group selected from methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 1; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is ethenyl; R⁵ and R^(5a) are both hydrogen; R⁶ ishydrogen, methyl, ethyl or chloro; Ar¹ is phenyl, thienyl, pyrrolyl,furanyl, or thiazolyl, each optionally substituted with a groupindependently selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.

Also preferred is a compound of the invention wherein X₁ and X₂ are bothC; p is 1; R¹ and R² are independently selected from the groupconsisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is ethenyl, —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ andR^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionallysubstituted with a group independently selected from methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.

The compounds of the invention can be prepared by a variety ofprocedures known in the art and those described below. The products ofeach step in the Scheme below can be recovered by conventional methodsincluding extraction, evaporation, precipitation, chromatography,filtration, trituration, crystallization, and the like. In the schemebelow all substituents, unless otherwise indicated, are as previouslydefined and suitable reagents are well known and appreciated in the art.

Scheme 1 depicts the reaction of an appropriate compound of formula (1)with an appropriate compound of formula (2) to give a compound offormula (1). The reaction in Scheme 1 can be carried out by at least twovariants discussed below.

In the first variant, an appropriate compound of formula (1) is one inwhich R¹, R², R³, p, R^(4b), R⁵, and R^(5a) are defined for formula I,and Y is —OH and an appropriate compound of formula (2) is one in whichR⁶, R⁷, each X, L₁, and Ar¹ are as defined in formula (I) or a groupwhich gives rise to R⁷ as defined in formula (1), for example, byformation of an ester, amide, sulfonamide, or acid.

For example, a compound of formula (1) is reacted with a compound offormula (2) in a Mitsunobu reaction using a suitable diazo reagent, suchas DEAD or ADDP, and the like, and a suitable phosphine reagent such astriphenyl phosphine or tributylphosphine, and the like. Such reactionsare carried out in a suitable solvent, such as toluene, tetrahydrofuran,and the like. Generally, the reactions are carried out at temperaturesof from about 0° C. to 50° C. Typical stoichiometry is for this reactionis, based on the compound of formula (1), about 1 to 2 equivalents of acompound of formula (2) and about 1 to 2 equivalents each of the diazoand phosphine reagents.

In the second variant, an appropriate compound of formula (1) is one inwhich R¹, R², R³, p, R^(4b), R⁵, and R^(5a) are defined for theinvention and Y is a leaving group and an appropriate compound offormula (2) is as defined above. Suitable leaving groups are well-knownin the art and include halides, particularly chloro, bromo, and iodo;and sulfonate esters, such as brosyl, tosyl, methanesulfonyl, andtrifluoromethanesulfonyl.

For example, a compound of formula (1) is reacted with a compound offormula (2) in a suitable solvent, such as acetonitrile,dimethylformamide, tetrahydrofuran, pyridine, methylethyl ketone and thelike. As will be readily appreciated an excess of a suitable base isusually used in the reaction, including sodium hydride, potassiumcarbonate, sodium carbonate, cesium carbonate, sodium bicarbonate,triethylamine, diisopropyethylamine. Such reactions generally arecarried out at temperatures of about room temperature to about thereflux temperature of the chosen solvent and typically use from about 1to 2 equivalents of the compound of formula (2).

In an optional step, a pharmaceutically acceptable salt of a compound offormula (1) is formed. The formation of such salts is well known andappreciated in the art.

As will be readily appreciated compounds of formula (1) and (2) can bereadily prepared by methods that are well-known and established in theart including methods and procedures similar to those described herein.For example, compounds of formula (1) are prepared by the reaction ofoptionally substituted phenyl azide with an acetylene ester followed byreduction or a protected hydroxy acetylene and optionally conversion toa leaving group and compounds of formula (2) are prepared bycarbon-carbon bond formation, reductive amination, coupling reaction,etc. Also, it is recognized that the steps required to prepare acompound of formula (2) can be carried out in any order, including afterreaction of a partial compound of formula (2) with a compound of formula(1), such that the later carried out carbon-carbon bond formation,reductive amination, coupling reaction, etc, provide a compound offormula I. As will be readily understood the steps to prepare thecompounds of formula I is dependent upon the particular compound beingsynthesized, the starting compound, and the relative liability of thesubstituted moieties. Also contemplated are various protection anddeprotection steps as may be required or beneficial for carrying out thereactions above. The selection and use of suitable protecting groups iswell known and appreciated in the art (see for example, ProtectingGroups in Organic Synthesis, Theodora Greene (Wiley-Interscience)).

The present invention is further illustrated by the following examplesand preparations. These examples and preparations are illustrative onlyand are not intended to limit the invention in any way. The terms usedin the examples and preparations have their normal meanings unlessotherwise designated. All chromatography is performed using silica gel,unless otherwise indicated.

Assay

The following assay protocols and results demonstrate the utility, invitro and in vivo efficacy of the compounds and/or methods of thecurrent invention and are provided for the purpose of illustration andnot meant to be limiting in any way.

The following abbreviations used herein are defined as follows. “LDL”is: Low Density Lipoprotein; “HDL” is High Density Lipoprotein; “VLDL”is Very Low Density Lipoprotein; “LDLR−/−” is Low Density Lipoproteinreceptor deficient; “DMEM” is Dulbecco's Modified Eagle's Medium;“GAPDH” is glyceraldehyde-3-phosphate dehydrogenase; “NaCMC” is sodiumcarboxymethylcellulose; “SLS” is sodium lauryl sulfate; “FPLC” is fastprotein liquid chromatography; “PBS” is phosphate buffered saline;“VLDL-C” is Very Low Density Lipoprotein-Cholesterol; “HDL-C” is HighDensity Lipoprotein-Cholesterol.

bDNA Assay for SHP mRNA

FXR is a key, direct transcriptional regulator of the Small HeterodimerPartner (SHP) gene, accession number NM_(—)021969, an atypical member ofthe nuclear receptor family that lacks a DNA-binding domain. SHPinteracts with several conventional and orphan members of the nuclearreceptor superfamily, including retinoid receptors and thyroid hormonereceptor. SHP inhibits transactivation potential of superfamily memberswith which it interacts. FXR and SHP both have been found to controlgenes involved in hepatic cholesterol catabolism, triglyceridesynthesis, and bile acid transport. Since FXR directly transactivatestranscription of the SHP gene, the SHP branched DNA method (bDNA)quantitates FXR activation by ligands. Thus, increased expression of SHPmRNA, as determined by increase bDNA signal, signifies engagement of FXRby an agonist.

Plate human hepatocarcinoma Huh7 cells grown in DMEM:F12 with 10% fetalbovine serum and in 96 well plate at the density of 1×10⁵/well. Afterovernight incubation, treat the cells with test compounds at variousconcentrations for 24 hours. Perform the bDNA assay according to themanufacturer protocol (Panomics, Fremont, Calif.) for the QuantiGene®High Volume Kit. After challenging the cells with a compound of theinvention, lyse the cells with QuantiGene® lysis buffer containing theSHP mRNA oligonucleotides described below. Appropriate bDNAoligonucleotide reagents (capture extenders (CEs), label extenders(LEs), and blockers (BLs)) may be designed and synthesized for detectinghuman SHP mRNA by Panomics (Fremont, Calif.).

Incubate the lysis buffer for 15-minute at 37° C., then transfer 100 μLof the lysate from each well to the corresponding wells of the captureplate. Incubate the capture plate overnight at 53° C. Wash the captureplate twice with QuantiGene® wash buffer followed by addition of 100μL/well QuantiGene® amplifier working reagent. Incubate the plate for 60minutes at 46° C. followed by two washes. Label the mRNA to be measuredby addition of 100 μL QuantiGene® label probe working buffer thenincubate for 60 minutes at 46° C. Wash the capture plate twice and add100 μL/well QuantiGene® substrate plus QuantiGene® enhancer reagent.Incubate the plates at 37° C. for up to 30 minutes and then read on aluminometer (Packard Fusion Alpha, 1 second detection) to detect theluminescent signal. Calculate EC₅₀ values i.e. effective responserelative to maximal response. Exemplified compounds are effective as FXRmodulators based on the above assay at an EC₅₀ of 2 uM or less. Forexample the compound of example 42 exhibits SHP gene activation EC₅₀ ofabout 370 nM.

LDLR−/− Serum Lipid Modulation

Acclimate animals for two weeks prior to study initiation. House miceindividually in polycarbonate cages with filter tops, and maintain miceon a 12:12 hour light-dark cycle (lights on at 6:00 AM) at 21° C.Provide deionized water ad libitum and maintain for two weeks on‘western diet’ TD 88137 Diet (42% fat, 0.15% cholesterol, Harlan Teklad)ad libitum. Optimize groups of five ten-week-old male LDLR−/− mice basedon serum triglyceride and cholesterol levels. Dose groups once daily byoral gavage with various doses of the test compound dissolved in 5%EtOH/5% Solutol in NaCMC (1%), SLS (0.5%), antifoam (0.05%), Povidone(0.085%) for seven days. At the end of the seven-day dosing period,collect blood by cardiac puncture after asphyxiation in a CO₂ chamber.Measure serum triglycerides, glucose, and total cholesterol usingstandard clinical chemistry instrumentation and reagents [Hitachi 912instrument with reagent kits (Roche, Indianapolis, Ind.)]. Assay pooledserum samples by FPLC analysis for lipoprotein cholesterol fractionvalues (VLDL, LDL, HDL) by separation on a size exclusion column within-line determination of cholesterol. Lipoproteins were separated byfast protein liquid chromatography, and cholesterol was quantitated withan in-line detection system. Briefly, 35 μL plasma samples/50 μL pooledsample was applied to a Superose 6 HR 10/30 size exclusion column(Amersham Pharmacia Biotech, Piscataway, N.J.) and eluted with PBS, pH7.4 (diluted 1:10), containing 5 mM EDTA, at 0.5 mL/min. Cholesterolreagent from Roche Diagnostics (Indianapolis, Ind.) at 0.16 mLl/min wasmixed with the column effluent through a T connection; the mixture wasthen passed through a 15 m×0.5 mm knitted tubing reactor (AuraIndustries, New York, N.Y.) immersed in a 37 C water bath. The coloredproduct produced in the presence of cholesterol was monitored in theflow stream at 505 nm, and the analog voltage from the monitor wasconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration was plottedvs. time, and the area under the curve corresponding to the elution ofVLDL-C and HDL-C was calculated using Turbochrome (version 4.12F12)software from PerkinElmer (Norwalk, Conn.).

In this assay, tested compounds of the invention reduce totalcholesterol up to 84% and triglycerides up to 86% when dosed at 10mg/kg. More specifically, the compound of Example 13 lowers totalcholesterol by 60% and triglycerides by 63% when dosed at 10 mg/kg.

The specific dose of a compound administered according to this inventionwill, of course, be determined by the particular circumstancessurrounding the case including, for example, the compound administered,the route of administration, the state of being of the patient, and thepathological condition being treated. A typical daily dose will containa nontoxic dosage level of from about 0.1 mg to about 1000 mg/day of acompound of the present invention.

The compounds of this invention may be administered by a variety ofroutes including oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal. These compounds preferably are formulatedprior to administration, the selection of which will be decided by theattending physician. Thus, another aspect of the present invention is apharmaceutical composition comprising an effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances.(Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co.(1990)). The pharmaceutical compositions of the present invention may beadapted for these various routes and may be administered to the patient,for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions. The total activeingredients in such composition comprises from 0.1% to 99.9% by weightof the formulation.

Compounds of the invention may be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for example, by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds may be formulated assustained release dosage forms and the like. The formulations can beconstituted such that they release the active ingredient only orpreferably in a particular physiological location, possibly over aperiod of time. The coatings, envelopes, and protective matrices may bemade, for example, from polymeric substances or waxes.

PREPARATIONS AND EXAMPLES

The following preparations and examples further illustrate theinvention.

The following abbreviations used herein are defined according toAldrichimica Acta, Vol 17, No. 1, 1984. Other abbreviations are definedas follows. “MeOH” is methanol; “EtOH” is ethanol; “EtOAc” is ethylacetate; “Et₂O” is diethyl ether; “hex” is hexane; “DCE” isdichloroethane; “TMSCHN₂” is (trimethylsilyl)diazomethane; “ADDP” is1,1-(Azodicarbonyl)dipiperidine; “dppf” is diphenylphosphinoferrocene;“dba” is dibenzylidineacetone; “THF” is tetrahydrofuran; “TBAF” istetrabutylammonium fluoride; “OAc” is acetate; “DCE” is dichloroethane.

All compounds are named using ChemDraw Ultra 7.0 available fromCambridgeSoft Corporation, Cambridge, Mass.

Preparations Preparation 1 2-Azido-1,3-dichloro-benzene Method 1

To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40mL) is added concentrated hydrochloric acid (12 mL). The reaction isstirred for 10 min. To this solution is added a solution of sodiumnitrite (2.55 g) in water (7.5 mL) over 3 min. Upon completion of theaddition, the reaction is stirred for an additional 30 min. A solutionof sodium azide (2.41 g) in water (8 mL) is added over 5 min. After 30min, pH 7 buffer (50 mL) is added and the reaction is transferred to aseparatory funnel. The layers are separated and the aqueous layer isextracted with ethyl acetate. The organic layers are combined and washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give the title compound (2.11 g). ¹H NMR (400 MHz,CDCl₃) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H)

Method 2

A solution of 2,6-dichloroaniline (100 g, 617 mmol) in MTBE (1 L) isadded via addition funnel over 30 minutes to commercial hydrogenchloride (600 mL). The white suspension is stirred 15 minutes and iscooled to 0° C. A solution of sodium nitrite (42.5 g, 617 mmol) in water(150 mL) is added dropwise via addition funnel. After stirring at 0° C.for 30 minutes, a solution of sodium azide (40.1 g, 617 mmol) in water(150 mL) is added. After the addition is completed (45 minutes), themixture is stirred at 5-10° C. for 30 minutes. The reaction mixture isbasified (pH 12) with 50% aq. NaOH, and is stirred for 30 more minutes.The phases are separated and the aqueous layer is extracted three timeswith MTBE. The combined organic layers are dried over magnesium sulfateand filtered. Toluene (1 L) is added to the organic layer and thesolution is concentrated under reduced pressure to a volume of 760 mL toyield the title compound (115 g, 100% conversion, 0.8M solution) as atoluene solution. ES/MS m/e 188 (M+1).

The following compounds are prepared essentially according to thepreparation of 2-Azido-1,3-dichloro-benzene via method 1 usingappropriate starting material. Preparation 1A:2-Azido-1-chloro-3-fluoro-benzene; Preparation 1B:1-Azido-2-trifluoromethoxy-benzene; Preparation 1C:1-Azido-2-trifluoromethyl-benzene.

Preparation 2 2-Azidomethyl-1,3-dichloro-benzene

To a solution of 2,6-dichlorobenzylbromide (0.50 g) in dimethylformamide(5 mL) is added sodium azide (0.41 g). The reaction is heated to 55° C.overnight. The resulting solution is cooled to room temperature and isconcentrated under reduced pressure. The residue is dissolved in ethylacetate, washed with water and brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure to give the titlecompound (0.37 g). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.40 (d, 2H),7.30-7.25 (t, 1H), 4.73 (s, 2H).

Preparation 3 4-Methyl-pent-2-ynoic Acid Ethyl Ester

To a solution of the isopropyl alkyne (6.32 g), cooled in adry-ice/acetone bath, in tetrahydrofuran (200 mL) is added 1.6 M N-butyllithium solution (63.8 mL). After 1 h, ethyl chloroformate (9.33 mL) isadded and the reaction mixture is stirred for an additional 1.5 h. Thereaction mixture is allowed to warm to room temperature and is quenchedwith saturated ammonium chloride solution. The reaction is extracted twotimes with ethyl acetate. The organic layers are combined, washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give the title compound (11.5 g). ¹H NMR (400 MHz,CDCl₃) δ 3.75 (s, 3H), 2.8-2.65 (m, 1H), 1.25-1.23 (d, 6H).

The following compound is prepared essentially according to thepreparation of 4-Methyl-pent-2-ynoic acid ethyl ester using theappropriate starting material. Preparation 3A: Cyclopropyl-propynoicacid methyl ester

Preparation 43-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazole-4-carboxylic AcidEthyl Ester

A solution of 2-azido-1,3-dichloro-benzene (1.0 g) and4-methyl-pent-2-ynoic acid ethyl ester (1.8 g) in toluene (5 mL) isheated to 120° C. overnight. Two regioisomers are observed in a range of1:1 to 3:1 in favor of the desired product. The reaction is concentratedunder reduced pressure and the residue is purified by flashchromatography, eluting with 5% ethyl acetate in hexanes. ¹H NMR (400MHz, CDCl₃) δ 7.48 (d, 2H), 7.42 (t, 1H), 4.22 (q, 2H), 3.64 (m, 1H),1.46 (d, 6H), 1.15 (t, 3H).

The following compounds are prepared by methods similar to thosedescribed in the preparation of3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazole-4-carboxylic acidethyl ester using the appropriate starting material.

Preparation 4A:5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazole-4-carboxylicacid methyl ester; Preparation 4B:3-(2,6-Dichloro-phenyl)-5-methyl-3H-[1,2,3]triazole-4-carboxylic acidmethyl ester: Preparation 4C:3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazole-4-carboxylic acidethyl ester; Preparation 4D:5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester; Preparation 4E:5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester Preparation 4F:5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazole-4-carboxylicacid methyl ester; Preparation 4G:5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester (64%), ES/MS m/e 342.0 (M+1).

Preparation 5[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol

To a 0° C. solution of3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazole-4-carboxylic acidethyl ester (2.88 g) in THF (25 mL) is added 1 M DIBAL in toluene (38mL). The reaction is allowed to warm to room temperature. Uponcompletion, the reaction mixture is quenched slowly with water and isacidified with 1 N HCl. The resulting solution is extracted two timeswith ethyl acetate. The combined organic layers are washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure to give the title compound (2.26 g). ES/MS (m/e) 284 (M+0), 286(M+2); mp: 154-155° C.

The following compounds are prepared essentially according to thepreparation of[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanolusing the appropriate starting material.

Preparation 5A:[3-(2,6-Dichloro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol, ¹HNMR (400 MHz, CDCl3) δ 7.54 (m, 3H), 4.57 (s, 2H), 2.48 (s, 3H);Preparation 5B:[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol,¹H NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.41 (dd, 1H), 7.24 (d, 1H),4.60 (q, 2H), 3.20 (m, 1H), 1.45 (d, 6H); Preparation 5C:[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol, ¹H NMR (400 MHz, CDCl3) δ 7.62 (m, 2H), 7.50(m, 2H), 4.60 (s, 2H), 3.19 (m, 1H), 1.41 (d, 6H); Preparation 5D:[5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol,¹H NMR (CDCl3) δ 7.87 (d, 1H), 7.72 (m, 2H), 7.51 (d, 1H), 4.54 (d, 2H),3.19 (m, 1H), 1.43 (d, 6H); Preparation 5E:[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanolES/MS (m/e): 284.0 (M+0), 286.0 (M+2); Preparation 5F:[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-yl]methanol(95%), ES/MS m/e 300.0 (M+1).

Preparation 6 5-Chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole

To a solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(0.100 g) in dichloromethane (2 mL) and carbon tetrachloride (2 mL) isadded triphenyl phosphine (0.275 g). Upon completion, the reaction isconcentrated under reduced pressure. The residue is dissolved indichloromethane to aid in loading solubility and is purified via filterchromatography eluting with 10% ethyl acetate in toluene to give thedesired product (0.091 g, 86%). ¹H NMR (400 MHz, CDCl3) δ 7.58-7.54 (d,2H), 7.52-7.50 (t, 1H), 4.48 (s, 2H), 3.24-3.21 (m, 1H), 1.51-1.49 (d,6H).

Preparation 7 3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazole-4-carbaldehydeStep A

A solution of 2-azido-1,3-dichloro-benzene (4.00 g, 1 equiv) and3-trimethylsilanyl-prop-2-yn-1-ol (6.29 mL, 2 equiv) in toluene (10 mL)is heated to 120° C. for 23 h. The reaction mixture is allowed to coolto room temperature and is diluted with 100 mL methylene chloride. Thesolution is adsorbed onto diatomaceous earth and is purified via flashchromatography eluting with hexanes/ethyl acetate (85:15 to 20:80) togive [3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (2.30 g,44%) as an off-white solid.

Step B

To a solution of[3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol (1.87 g, 1equiv) in methylene chloride (110 mL) is added Dess-Martin oxidant (4.20g, 1.3 equiv). The reaction mixture is allowed to stir at roomtemperature for 3 h. The reaction is incomplete as evidenced by TLC. Thereaction mixture is treated with Dess-Martin oxidant (1.20 g). Thereaction mixture is allowed to stir at room temperature for anadditional 2 h. The reaction mixture is treated with 80 mL 1.5 N sodiumhydroxide and 40 mL diethyl ether. The resulting solution is allowed tostir at room temperature for ten minutes. The reaction mixture isdiluted with 120 mL water and extracted three times with chloroform. Thecombined organic layers are dried over magnesium sulfate and filteredthough a plug of silica gel eluting with chloroform/ethyl acetate (3:1,200 mL). The filtrate is concentrated under reduced pressure to give thetitle compound (1.76 g, 94%) as a white solid.

Preparation 8 Methanesulfonic acid3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethyl Ester

To a solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(0.100 g) in dichloromethane (2 mL) is added Et₃N (0.25 mL) followed bymethanesulfonyl chloride (0.075 mL). The reaction mixture is stirred atroom temperature for 2 h. The reaction is diluted with ethyl acetate (20mL) and washed with water (2×20 mL). The organic layer is dried (Na₂SO₄)and concentrated under reduced pressure to give the title compound (101mg). ¹H NMR (400 MHz, CDCl₃): δ 7.40-7.60 (m, 3H), 5.10 (s, 2H),3.20-3.30 (m, 1H), 2.85 (s, 3H), and 1.40-1.50 (d, 6H).

Preparation 95-(4-Bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole

To a solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(300 mg, 1.05 mmol) in toluene (4 mL) are added 4-bromo-3-methyl-phenol(196 mg, 1.05 mmol) and tri-n-butylphosphine (394 μL, 1.58 mmol). Thereaction mixture is cooled to 0° C. To the reaction mixture is added1,1′-(Azocarbonyl)-dipiperidine (399 mg, 1.58 mmol) and the reactionmixture is warmed to room temperature. After 6 h, the reaction mixtureis concentrated and the residue is chromatographed eluting with 10% to20% EtOAc/hexanes to yield the title compound (324 mg, 68%). LC-ES/MSm/e 455.7 (M+1)

The following compounds are prepared essentially according to thepreparation of5-(4-Bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazoleusing the appropriate starting material.

Preparation 9A:1-(2,6-Dichloro-phenyl)-5-(4-iodo-phenoxymethyl)-4-isopropyl-1H-[1,2,3]triazole,LC-ES/MS m/e 488.0 (M+1), ¹H NMR (300 MHz, CDCl₃) δ 7.5 (m, 5H), 6.5 (d,2H), 4.9 (s, 2H), 3.2 (p, 1H), 1.4 (d, 6H); Preparation 9B:1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone,LC-ES/MS m/e 418.0 (M+1); Preparation9C₁-{4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanoneLC-ES/MS m/e 402.0 (M+1); Preparation 9D,2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-propan-2-ol;Preparation 9E,6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indole-3-carboxylicacid methyl ester, ES/MS m/e 590.8 (M+1).

Preparation 10 1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanol

To a 0° C. solution of1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone(314 mg, 0.751 mmol) in THF/MeOH (6 mL/1 mL) is added sodium borohydride(116 mg, 3.04 mmol). The reaction is warmed to room temperatureovernight. The reaction is concentrated and the residue is partitionedbetween EtOAc (100 mL) and 1 N HCl (20 mL). The aqueous layer isextracted with EtOAc (100 mL) and the combined organic layers are washedwith brine, dried (MgSO₄), filtered, and concentrated under reducedpressure. The residue is purified via chromatography (40 g SiO₂, 20% to40% EtOAC/Hexanes) to yield the title compound (298 mg, 94%). LC-ES/MSm/e 419.7 (M+1).

The following compound is prepared essentially according to thepreparation of1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanolusing the appropriate starting material.

Preparation 10A:1-{4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanol.

Preparation 112-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-ol

To a −78° C. solution of1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone(500 mg, 1.19 mmol) in THF (12 mL) is added methylmagnesium bromide (2.0mL, 5.98 mmol, 3.0 M in THF) dropwise. The reaction mixture is warmed toroom temperature. After 4 h, the reaction is cooled to 0° C., quenchedwith NH₄Cl and warmed to room temperature. The reaction mixture isconcentrated and the residue is partitioned between Et₂O and 1N HCl. Theaqueous layer is extracted with Et₂O and the combined organic layers arewashed with brine, dried (MgSO₄), filtered, concentrated andchromatographed eluting with 0% to 30% EtOAC/Hexane to yield the titlecompound (414 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.46 (m, 2H),7.43-7.38 (m, 1H), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89 (s,2H), 3.20 (sept, 1H, J=6.6 Hz), 2.04 (s, 3H), 1.53 (s, 6H), 1.45 (d, 6H,J=6.6 Hz).

The following compounds are prepared essentially according to thepreparation of2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-olusing the appropriate starting material.

Preparation 11A:2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-propan-2-ol,¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, 1H, J=1.3 Hz), 7.46 (s, 1H), 7.39(dd, 1H, J=9.2, 7.0 Hz), 7.35 (d, 2H, J=8.8 Hz), 6.73 (d, 2H, J=8.8 Hz),4.90 (s, 2H), 3.19 (sept, 1H, J=7.0 Hz), 1.54 (s, 6H), 1.44 (d, 6H,J=7.0 Hz); Preparation 11B:2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-propan-2-ol,¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, 1H, J=1.8 Hz), 7.46 (s, 1H), 7.40(dd, 1H, J=9.2, 6.6 Hz), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89(s, 2H), 3.21 (sept, 1H, J=7.0 Hz), 2.04 (s, 3H), 1.54 (s, 6H), 1.45 (d,6H, J=7.0 Hz).

Preparation 123-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol

A mixture of tricyclohexylphosphine (525 mg, 1.87 mmol), palladiumbis(dibenzylidine)acetone (460 mg, 0.801 mmol) and dioxane (200 ml) isstirred at room temperature for one half hour. Added are4-bromo-3-methyl-phenol (5.00 g, 26.7 mmol), pinacolborane (7.45 g, 40.1mmol) and potassium acetate (3.93 g, 40.1 mmol). The reaction mixture isheated to 80° C. for 20 hours and is cooled to room temperature. Thereaction mixture is diluted with water and extracted with ether. Thecombined ether fractions are washed with brine, dried (MgSO₄) andevaporated. The residue is purified using flash chromatography on silicagel eluting with 0 to 2% MeOH/CH₂Cl₂, to yield g the title compound (1.6g, 47%). An additional 2.76 g of the title compound is provided by asecond purification of impure fractions by flash chromatography to yielda total of 4.36 g (70%) of the title compound. ES/MS m/e 233.3 (M−1).

Preparation 13 6-Bromo-1H-indole-3-carboxylic Acid Methyl Ester

To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) inmethanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solutionin hexanes, ca 9 mL) over two minutes at room temperature. The yellowmixture is concentrated under reduced pressure. The residue isredissolved in methanol and concentrated under reduced pressure. Thisprocess is repeated several times to give the title compound as a solid(100%). ES/MS m/e 256.0 (M+2).

The following compound is prepared essentially according to thepreparation of 6-bromo-1H-indole-3-carboxylic acid methyl ester usingthe appropriate starting material. Preparation 13A:6-Bromo-benzo[b]thiophene-2-carboxylic acid methyl ester, ¹H NMR (400MHz, CDCl₃) δ 7.99 (m, 2H), 7.70 (d, 1H), 7.50 (d, 1H), 3.92 (s, 3H);

Preparation 14 6-Bromo-1-methyl-1H-indole-3-carboxylic Acid Methyl Ester

To a mixture of 5-bromo-1H-indole-3-carboxylic acid methyl ester (100mg, 0.394 mmol), potassium carbonate (163 mg, 1.18 mmol) in DMF is addediodomethane (30 μL, 0.47 mmol). The reaction mixture is stirred for 1.5hours. Additional iodomethane (10 μL) is added and the reaction isstirred for 30 minutes. The reaction mixture is diluted withdichloromethane and filtered. The filtrate is concentrated under highvacuum, diluted with ethyl acetate, and concentrated to give 105 mg(99%) of the title compound. ES/MS m/e 270.0 (M+2).

The following compound is prepared essentially according to thepreparation of 6-bromo-1-methyl-1H-indole-3-carboxylic acid methylester, using the appropriate starting material.

Preparation 14A: 6-Bromo-1-isopropyl-1H-indole-3-carboxylic acid methylester, ¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, 1H), 7.88 (s, 1H), 7.53 (s,1H), 7.33 (dd, 1H), 4.64-4.33 (m, 1H), 3.88 (s, 3H), 1.52 (d, 6H).

Preparation 156-(4-Hydroxy-2-methyl-phenyl)-1-methyl-1H-indole-3-carboxylic AcidMethyl Ester

A mixture of3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (105mg, 0.448 mmol), (6-bromo-1H-indol-3-yl)-acetic acid methyl ester (100mg, 0.373 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021mmol), DMF (1.2 mL), ethanol (0.6 mL) and 2M aqueous potassium carbonate(0.6 mL) is heated to 80° C. for 6 hours. The reaction is cooled to roomtemperature, diluted with water, and acidified with 1 N HCl. Theresulting solution is extracted with CH₂Cl₂. The combined organic layersare dried over anhydrous magnesium sulfate and concentrated. The residueis purified via radial chromatography eluting with CH₂Cl₂. A secondpurification of impure fractions is performed via radial chromatographyeluting with 2% MeOH—CH₂Cl₂ to provide (78 mg, 74%) of the titlecompound. LC-ES/MS m/e 296.0 (M+1).

The following compounds are prepared essentially according to thepreparation of6-(4-Hydroxy-2-methyl-phenyl)-1-methyl-1H-indole-3-carboxylic acidmethyl ester using the appropriate starting material.

Preparation 15A:6-(4-Hydroxy-2-methyl-phenyl)-benzo[b]thiophene-3-carboxylic acid methylester; Preparation 15B:6-(4-hydroxy-2-methyl-phenyl)-benzo[b]thiophene-2-carboxylic acid methylester, utilizing a 7:3 mixture of 6-bromo-benzo[b]thiophene-3-carboxylicacid methyl ester and 6-bromo-benzo[b]thiophene-2-carboxylic acid methylester, ES/MS m/e 297.0 (M−1); Preparation 15C:6-(4-Hydroxy-2-methyl-phenyl)-benzo[b]thiophene-2-carboxylic acid methylester, ES/MS m/e 297.3 (M−1); Preparation 15E:6-(4-Hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indole-3-carboxylic acidmethyl ester, ES/MS m/e 322.2 (M−1); Preparation 15D:6-(4-Hydroxy-2-methyl-phenyl)-benzo[b]thiophene-2-carboxylic acid methylester, ES/MS m/e 297.3 (M−1).

Preparation 16 2- and 3-acetyl-6-bromobenzothiophene

To a solution of 6-bromobenzothiophene (20 g, 93.8 mmol) and acetylchloride (8.84 g, 112.6 mmol) in 1,2-dichloroethane (120 mL) is addeddropwise at room temperature, tin tetrachloride (1M in dichloromethane,112.6 mmol, 112.6 mL) under nitrogen. After the addition is completed,the reaction mixture is stirred at room temperature overnight. Themixture is poured onto an ice/water bath and extracted withdichloromethane. The organic phase is washed with saturated NaHCO₃,water, and brine, dried over MgSO₄, and evaporated under reducedpressure. The crude residue is purifed by flash chromatography on silicagel eluting with hexane/EtOAc 6:1 as eluent mixture. The title compound(12 g, 50%) is obtained as a 7:3 mixture of the two isomers:3-acetyl-6-bromobenzothiophene and 2-acetyl-6-bromobenzothiophene. ES/MSm/e 256 (M+2).

Preparation 17 6-Bromobenzothiophene-3-carboxylic acid and6-Bromobenzothiophene-2-carboxylic Acid

To a 0° C. solution of sodium hydroxide (13.64 g, 341 mmol) in water (94mL) is added slowly bromine (21.92 g, 137.18 mmol). The reaction mixtureis stirred at 0° C. for 15 minutes. To the reaction mixture is addeddropwise a solution of the mixture of 3-acetyl-6-bromobenzothiophene and2-acetyl-6-bromobenzothiophene (10.00 g, 39.19 mmol) in dioxane (75 mL).The reaction mixture is stirred at room temperature for 2 hours. Asolution of NaHSO₃ (40%, 50 mL) is added followed by HCl (10 mL) to givean orange solid. The solid is filtered off, and washed with waterfollowed by hexanes to give 7 g (70%) of the mixture of both acids:6-Bromobenzothiophene-3-carboxylic acid and6-Bromobenzothiophene-2-carboxylic acid in a ratio 7:3. ES/MS m/e 258(M+2).

Preparation 18 6-Bromobenzothiophene-3-carboxylic Acid Methyl Ester and6-Bromobenzothiophene-2-carboxylic Acid Methyl Ester

A solution of the mixture of 6-Bromobenzothiophene-3-carboxylic acid and6-Bromobenzothiophene-2-carboxylic acid (6.5 g, 25.28 mmol) and sulfuricacid (4.65 g, 47.43 mmol) in MeOH (100 mL) is heated to 65° C.overnight. A light brown solid is visualized. The solution is cooled toroom temperature and the solid formed is filtered off and washed withMeOH to give 5.6 g (83%) of the mixture of:6-Bromobenzothiophene-3-carboxylic acid methyl ester and6-Bromobenzothiophene-2-carboxylic acid methyl ester in a ratio 7:3.ES/MS m/e 272 (M+2).

Preparation 19 2′-Bromo-4′-hydroxy-biphenyl-4-carboxylic Acid MethylEster Step A

To 4′-methoxy-2′-nitro-biphenyl-4-carboxylic acid methyl ester (4.00 g)suspended in ethanol (150 mL) and ethyl acetate (150 mL) is added 5%palladium on carbon (0.300 g). The reaction mixture is placed under anatmosphere of hydrogen (50 psi) and shaken on a Parr apparatus. After 18h, the reaction mixture is degassed with nitrogen and filtered though aplug of silica gel, eluting with 700 mL ethyl acetate and 600 mLmethylene chloride. The filtrate is evaporated to give2′-amino-4′-methoxy-biphenyl-4-carboxylic acid methyl ester (3.52g, >99%) as a white solid.

Step B

To a solution of sodium nitrite (1.40 g) in dimethyl sulfoxide (50 mL)is added 2′-amino-4′-methoxy-biphenyl-4-carboxylic acid methyl ester(2.61 g). After 5 minutes, the reaction mixture is treated with asolution of 4.7 mL hydrobromic acid (48%) in 50 mL dimethyl sulfoxide.The reaction is allowed to stir at room temperature for 2 h. Thereaction mixture is diluted with a solution of 20.0 g potassiumcarbonate dissolved in 400 mL water. The product is extracted five timeswith methylene chloride. The combined organic layers are dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue is chromatographed eluting with hexanes/ethyl acetate (99:1to 86:14) to give 2′-bromo-4′-methoxy-biphenyl-4-carboxylic acid methylester (1.00 g, 31%) as a white solid.

Step C

To a 0° C. solution of 2′-bromo-4′-methoxy-biphenyl-4-carboxylic acidmethyl ester (0.200 g) in methylene chloride (5 mL) is added borontribromide (0.176 mL). The reaction mixture is maintained at 0° C. for 2h. The reaction mixture is slowly quenched with 50 mL methanol, dilutedwith 150 mL 2N hydrochloric acid, and extracted three times withmethylene chloride. The combined organic layers are dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to give thetitle compound (0.180 g, 94%).

Preparation 20 4′-Hydroxy-2′-methyl-biphenyl-4-carboxylic Acid MethylEster

To a solution of 4-bromo-3-methyl phenol (0.300 g, 1 equiv) in DMF (5mL) are added 4-methylester phenyl boronic acid (0.58 g, 2 equiv), dppf(0.27 g, 0.3 equiv), palladium acetate (0.036 g, 0.1 equiv), and cesiumcarbonate (1.04 g, 2 equiv). The reaction mixture is heated to 75° C.for 1 h. The reaction is cooled to room temperature and is diluted withwater. The resulting solution is extracted with ethyl acetate. Thecombined organic layers are combined and washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Thecrude residue is purified via flash chromatography eluting with 3% ethylacetate in toluene to give the desired product (0.224 g, 58%). ES/MS m/e241.3 (M−1)

The following list is prepared essentially according to the preparationof 4′-Hydroxy-2′-methyl-biphenyl-4-carboxylic acid methyl ester usingthe appropriate starting material.

Preparation 20A: 4′-Hydroxy-3′-methyl-biphenyl-4-carboxylic acid methylester;

Preparation 20B: 2′-chloro-4′-hydroxy-biphenyl-4-carboxylic acid methylester;

Preparation 20C: 2′-Fluoro-4′-hydroxy-biphenyl-4-carboxylic acid methylester;

Preparation 20D: 4′-hydroxy-2′-trifluoromethyl-biphenyl-4-carboxylicacid methyl ester;

Preparation 20E: 4′-Hydroxy-2′-nitro-biphenyl-4-carboxylic acid methylester′

Preparation 21 Trifluoro-methanesulfonic acid2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl Ester

To a solution of 2-(4-methoxy-phenyl)-benzo[b]thiophen-6-ol (512 mg, 2mmol) in dichloromethane (20 mL) at 0° C. is added triethylamine (0.58mL, 5 mmol) and trifluoromethanesulfonic anhydride (0.67 mL, 4 mmol).The reaction is stirred at ambient temperature overnight. The reactionmixture is concentrated and the residue is redissolved in EtOAc, iswashed with 1N NaOH followed by 1N HCl. The organic layer isconcentrated to give the title compound (800 mg).

Preparation 22 2-(4-Methoxy-phenyl)-benzo[b]thiophene-6-carboxylic AcidMethyl Ester

A mixture of trifluoro-methanesulfonic acid2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester (750 mg), palladiumacetate (43 mg), 1,4-bis(diphenylphosphino)butane (97 mg), triethylamine(1.4 mL) in MeOH (8 mL) and DMSO (12 mL) is stirred under an atmosphereof carbon monoxide (100 psi) at 80° C. for 4 h. The reaction mixture isfiltered though a diatomaceous earth pad and the filtrate isconcentrated. The residue is purified by column chromatography on silicagel eluting with 0 to 20% EtOAc in hexanes to give the title compound(500 mg, 87%). LC-ES/MS m/e 321 (M+Na).

Preparation 23 2-(4-Hydroxy-phenyl)-benzo[b]thiophene-6-carboxylic AcidMethyl Ester

To a solution of 2-(4-methoxy-phenyl)-benzo[b]thiophene-6-carboxylicacid methyl ester (500 mg, 1.7 mmol) in dichloromethane (15 mL) at 0° C.is added BBr₃ (4.2 mL, 1 M in dichloromethane). The reaction mixture isstirred at ambient temperature overnight. The reaction is quenched bythe addition of methanol and concentrated under reduced pressure. Theresidue is partitioned between EtOAc and 1 N HCl. The organic layer isconcentrated and the residue is purified via chromatography eluting with0 to 25% EtOAc in hexanes to give the title compound (57 mg, 12%) as atan solid. LC-ES/MS m/e 283 (M−1).

Preparation 245-(4-Hydroxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic AcidMethyl Ester Step A

To a mixture of 4-methoxy-2-methylphenylboronic acid (912 mg, 6 mmol),5-bromo-4-methyl-thiophene-2-carboxylic acid methyl ester (1.1 g, 5mmol) and K₂CO₃ (1.38 g, 10 mmol) in toluene (30 mL) and water (5 mL) isbubbled N₂ for 15 minutes followed by addition oftetrakis(triphenylphosphine) palladium (289 mg, 0.25 mmol). The reactionmixture is stirred at 80° C. under N₂ overnight. The reaction mixture isfiltered through a diatomaceous earth pad eluting with EtOAc. Thecombined filtrate is concentrated and the residue is purified by columnchromatography on silica gel eluting with 0-15% EtOAc in hexanes to give5-(4-methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acidmethyl ester (540 mg, 39%). ¹H NMR (CDCl₃): δ 7.63 (s, 1H), 7.15 (d, 1H,J=8.4 Hz), 6.82 (d, 1H, J=2.8 Hz), 6.78 (dd, 1H, J=2.8, J=8.4 Hz), 4.79(bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H).

Step B

To a 0° C. solution of5-(4-methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acidmethyl ester (540 mg, 2 mmol) in dichloromethane (30 mL) is added BBr₃in dichloromethane (1N, 5.0 mL) and the mixture is stirred at ambienttemperature overnight. The reaction is quenched by addition of methanoland evaporated. The residue is purified by column chromatography onsilica gel eluting with 0-20% EtOAc in hexanes to give the titlecompound (420 mg, 82%). ¹H NMR (CDCl₃): δ 7.62 (s, 1H), 7.10 (d, 1H,J=7.9 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J=7.9 Hz), 4.79 (bs, 1H), 3.88 (s,3H), 2.15 (s, 3H), 2.02 (s, 3H).

The following compounds are prepared essentially according to thepreparation5-(4-hydroxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acidmethyl ester using the appropriate starting material.

Preparation 24A: 5-(4-Hydroxy-phenyl)-thiophene-2-carboxylic acid methylester, ¹H NMR (DMSO-d₆): δ 9.87 (s, 1H), 7.74 (d, 1H, J=4.0 Hz), 7.57(d, 2H, J=8.8 Hz), 7.40 (d, 1H, J=4.0 Hz), 6.83 (d, 2H, J=8.8 Hz), 3.81(s, 3H).

Preparation 24B: 5-(4-Hydroxy-2-methyl-phenyl)-thiophene-2-carboxylicacid methyl ester, ¹H NMR (DMSO-d₆): δ 9.71 (s, 1H), 7.76 (d, 1H, J=3.5Hz), 7.26 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=4.0 Hz), 6.72 (d, 1H, J=2.6Hz), 6.67 (dd, 1H, J=2.6, J=8.4 Hz), 3.81 (s, 3H), 2.32 (s, 3H).

Preparation 254-{[(4-Hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-benzoic AcidMethyl Ester

To an ambient temperature solution of 4-amino-3-methyl-phenol (1.0 g,8.12 mmol) in MeOH (77 mL) is added 4-formyl-benzoic acid methyl ester(1.47 g, 8.93 mmol) and decaborane (329 mg, 2.68 mmol). The reaction isstirred at room temperature. After 2 h, formaldehyde (1.23 mL, 16.93mmol, 37% in water) and decaborane (329 mg, 2.68 mmol) are added to thereaction. The reaction mixture is stirred overnight. The reactionmixture is concentrated under reduced pressure and the residue ispurified via chromatography to yield the title compound (2.07 g, 90%).LC-ES/MS m/e 286.2 (M+1).

The following compound is prepared essentially according to thepreparation54-{[(4-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-benzoic acidmethyl ester using the appropriate starting material

Preparation 25A:3-{[(4-Hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-benzoic acidmethyl ester (74%), LC-ES/MS m/e 286.2 (M+1); Preparation 25 B:4-{[(4-Hydroxy-2-methyl-phenyl)-methyl-amino]methyl}-2-trifluoromethyl-benzoicacid methyl ester (35% yield), LC-ES/MS m/e 340.0 (M+1).

Preparation 26 3-[2-(2-Chloro-4-hydroxy-phenyl)-vinyl]-benzoic AcidMethyl Ester

To a solution of 3-vinylbenzoic acid methyl (0.300 g) ester indimethylformamide (3 mL) are added 4-bromo-3-methyl phenol (0.35 g),tri(orthotoluyl)phosphine (0.06 g), Pd(dba)₂ (0.032 g), andtriethylamine (0.26 mL). The reaction is heated to 100° C. overnight.Upon cooling to room temperature, the solvent is evaporated underreduced pressure. The residue is dissolved in ethyl acetate, washed withwater and brine, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue is purified via filterchromatography on silica gel eluting with 300 mL toluene followed by 250mL 10% ethyl acetate in toluene to give the title compound (0.210 g). ¹HNMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.95-7.93 (d, 1H), 7.71-7.69 (d,1H), 7.53-7.51 (d, 1H), 7.48-7.44 (t, 1H), 7.38-7.34 (d, 1H), 6.96-6.92(d, 1H), 6.77-6.72 (m, 2H), 5.26 (broad s, 1H), 3.99 (s, 3H), 2.43 (s,3H).

Preparation 27 2-Trimethylsilanylethynyl-benzoic Acid Methyl Ester

To a solution of 2-iodo-benzoic acid methyl ester (792 mg, 3.02 mmol) inDMF (10 mL) are added trimethylsilylacetylene (854 μL, 6.04 mmol) andtriethylamine (2.95 mL, 21.1 mmol). The reaction mixture is degassed for20 minutes with a stream of nitrogen. Dichloro(bistriphenylphosphene)palladium (II) (212 mg, 0.302 mmol, 10 mol %) and copper (I) iodide (58mg, 0.302 mmol, 10 mol %) are added and the reaction is heated to 80° C.After 3 h, the reaction is concentrated and the residue ischromatographed eluting with 0 to 5% EtOAc/Hexanes to yield the titlecompound (597 mg, 85%). GC/MS: 232.

The following list of compounds is prepared essentially according to thepreparation of 2-trimethylsilanylethynyl-benzoic acid methyl ester usingthe appropriate starting material.

Preparation 27A: 3-Trimethylsilanylethynyl-benzoic acid methyl ester,GC/MS: 232; 4;

Preparation 27B: Trimethylsilanylethynyl-benzoic acid methyl ester,GC/MS: 232.

Preparation 28 2-Ethynyl-benzoic Acid Methyl Ester

To a solution of 2-trimethylsilanylethynyl-benzoic acid methyl ester(540 mg, 2.32 mmol) in acetonitrile/water (20 mL/5 mL) is added cesiumfluoride (1.41 g, 9.30 mmol). The reaction is stirred at roomtemperature. After 4 h, the reaction is concentrated and the residue ispartitioned between EtOAc (100 mL) and 0.2N HCl (30 mL). The aqueouslayer is extracted with EtOAc (100 mL) and the combined organic layersare washed with brine, dried (MgSO₄), filtered, and concentrated. Theresidue is chromatographed eluting with 0 to 5% EtOAc/Hexanes to yieldthe title compound (358 mg, 96%). GC/MS: 160.

The following compound is prepared essentially according to thepreparation of 2-ethynyl-benzoic acid methyl ester using the appropriatestarting material.

Preparation 28A: 3-Ethynyl-benzoic acid methyl ester, GC/MS: 160;Preparation 28B: 4-Ethynyl-benzoic acid methyl ester, GC/MS: 160.

Preparation 29 (4-Mercapto-phenyl)-acetic Acid Methyl Ester

To an ambient temperature solution of 4-mercaptophenylacetic acid (5.0g, 29.72 mmol) in MeOH (250 mL) is added sulfuric acid (1.25 mL). Thereaction is stirred at room temperature overnight. The reaction mixtureis concentrated and the residue is partitioned between Et₂O and water.The aqueous layer is extracted with Et₂O and the combined organic layersare washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed eluting with 0% to 30% EtOAC/Hexane to yield the titlecompound (3.69 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, 2H, J=7.9Hz), 7.12 (d, 2H, J=8.4 Hz), 3.66 (s, 3H), 3.54 (s, 2H).

Preparation 30 3-(4-Hydroxy-2-methyl-benzylamino)-benzoic Acid EthylEster Step A

A mixture of 2-methyl-4-benzyloxy benzaldehyde (1.22 g, 5.39 mmol) andethyl-3-amino benzoate (912 mg, 5.52 mmol) in glacial acetic acid (40mL) is stirred for 30 minutes. To the mixture, sodium triacetoxyborohydride (1.25 g, 5.90 mmol) is added. After 20 hours, the mixture isconcentrated and partitioned between ethyl acetate and saturated sodiumbicarbonate. The layers are separated and the aqueous layer is extractedwith ethyl acetate (2×). The combined ethyl acetate layers are dried(MgSO₄) and concentrated. The residue is purified by flashchromatography on 120 g silica with ethyl acetate in heptane gradient toprovide benzyl intermediate (1.6 g, 80%).

Step B

To a solution of the benzyl intermediate from Step A (471 mg, 1.25 mmol)in ethyl acetate (20 mL) under nitrogen is added 10% palladium on carbon(80 mg). The reaction vessel is evacuated and filled with hydrogen(balloon) and stirred under hydrogen over night. The mixture is filteredover diatomaceous earth and concentrated under reduced pressure toprovide the title product (300 mg, 84%). MS: 284.3 (M−1).

The following compound is prepared essentially according to thepreparation of 3-(4-hydroxy-2-methyl-benzylamino)-benzoic acid ethylester using the appropriate starting material.

Preparation 30A: 4-(4-Hydroxy-2-methyl-benzylamino)-benzoic acid methylester, (546 mg, 91%), ES/MS m/e 270.3 (M−1)

Preparation 311-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone

To a 0° C. suspension of 4′-hydroxy-2′-methylacetophenone (969 mg, 6.45mmol),[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(1.85 g, 6.45 mmol), tri-n-butylphosphine (2.42 ml, 9.73 mmol) intoluene (20 mL) is added ADDP (2.46 g, 9.73 mmol). The reaction mixtureis warmed to room temperature and stirred overnight. The reactionmixture is concentrated and the residue is chromatographed eluting with0% to 30% EtOAc/Hex to yield the title compound (1.71 mg, 63%). ¹H NMR(400 MHz, CDCl₃) δ 7.75 (dd, 1H, J=8.5, 2.1 Hz), 7.72 (d, 1H, J=1.3 Hz),7.49 (d, 1H, J=2.2 Hz), 7.47 (s, 1H), 7.41 (dd, 1H, J=9.2, 6.6 Hz), 6.78(d, 1H, J=8.4 Hz), 4.99 (s, 2H), 3.22 (sept, 1H, J=7.0 Hz), 2.52 (s,3H), 2.06 (s, 3H), 1.46 (d, 6H, J=7.0 Hz).

The following list of compounds is prepared essentially according to thepreparation of1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanoneusing the appropriate starting material. Preparation 31A:1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-ethanone(88%), ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, 2H, J=8.8 Hz), 7.48 (d, 1H,J=1.8 Hz), 7.46 (s, 1H), 7.39 (dd, 1H, J=9.0, 6.8 Hz), 6.80 (d, 2H,J=8.8 Hz), 4.98 (s, 2H), 3.21 (sept, 1H, J=7.0 Hz), 2.53 (s, 3H), 1.45(d, 6H, J=7.0 Hz); Preparation 31 B:1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-ethanone(89%), ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, 1H, J=8.5, 0.1 Hz), 7.72 (d,1H, J=1.9 Hz), 7.49 (d, 1H, J=1.8 Hz), 7.47 (s, 1H), 7.42 (dd, 1H,J=9.2, 6.6 Hz), 6.78 (d, 1H, J=8.8 Hz), 4.99 (s, 2H), 3.22 (sept, 1H,J=7.0 Hz), 2.52 (s, 3H), 2.06 (s, 3H), 1.46 (d, 6H, J=7.0 Hz);Preparation 31C:4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonitrile,ES/MS m/e (35Cl) 463 (M+1).

Preparation 322-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-ol

To a −78° C. solution of1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone(500 mg, 1.19 mmol) in THF (12 mL) is added methylmagnesium bromide (2.0mL, 5.98 mmol, 3.0 M in THF) dropwise. The reaction mixture is warmed toroom temperature. After 4 h, the reaction is cooled to 0° C., quenchedwith NH₄Cl, and warmed to room temperature. The reaction mixture isconcentrated and the residue is partitioned between Et₂O and 1N HCl. Theaqueous layer is extracted with Et₂O and the combined organic layers arewashed with brine, dried (MgSO₄), filtered, concentrated andchromatographed eluting with 0% to 30% EtOAC/Hexane to yield the titlecompound (414 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.46 (m, 2H),7.43-7.38 (m, 1H), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89 (s,2H), 3.20 (sept, 1H, J=6.6 Hz), 2.04 (s, 3H), 1.53 (s, 6H), 1.45 (d, 6H,J=6.6 Hz).

The following list of compounds is prepared essentially according to thepreparation of2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-olusing the appropriate starting material. Preparation 32A:2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-propan-2-ol(63%), ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, 1H, J=1.3 Hz), 7.46 (s, 1H),7.39 (dd, 1H, J=9.2, 7.0 Hz), 7.35 (d, 2H, J=8.8 Hz), 6.73 (d, 2H, J=8.8Hz), 4.90 (s, 2H), 3.19 (sept, 1H, J=7.0 Hz), 1.54 (s, 6H), 1.44 (d, 6H,J=7.0 Hz); Preparation 32B:2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-propan-2-ol(58%), ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, 1H, J=1.8 Hz), 7.46 (s, 1H),7.40 (dd, 1H, J=9.2, 6.6 Hz), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz),4.89 (s, 2H), 3.21 (sept, 1H, J=7.0 Hz), 2.04 (s, 3H), 1.54 (s, 6H),1.45 (d, 6H, J=7.0 Hz).

Preparation 33 4-Formyl-2-methyl-benzoic Acid Methyl Ester Step A

To a solution of 4-iodo-3-methyl-benzoic acid (5.2 g, 20 mmol) in THF(30 mL), is added 2.0 M borane-dimethyl sulfide complex in THF (40.0 mL,80 mmol) dropwise. The reaction mixture is stirred overnight. Thereaction mixture is quenched carefully at 0° C. with methanol (20 mL)and the mixture is evaporated to dryness under reduced pressure. Theresidue is partitioned between EtOAc (80 mL) and water (60 mL). Theorganic phase is washed with brine (60 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure to a residue. The residue ispurified by flash chromatography (AnaLogix, gradient EtOAc/Hexane) togive (4-Iodo-3-methyl-phenyl)-methanol as white solid (4.7 g, 95%).¹HNMR (CDCl₃) (ppm): 2.4 (3H, s), 4.55 (2H, s), 6.8-7.75 (3H, m).

Step B

To a 50 mL hastalloy Parr pressure reactor is charged palladium acetate(0.161 g, 0.7 mmol, 1,4 bis-(diphenylphosphino)butane (DPPB) (0.363 g,0.85 mmol), (4-Iodo-3-methyl-phenyl)-methanol (1.80 g, 7.25 mmol), drymethanol (10.0 ml), dry triethylamine (5.25 ml, 37.7 mmol) and dryacetonitrile (15.0 ml). The reaction vessel is evacuated and filled withnitrogen (4×). Next the reaction vessel is evacuated and filled withcarbon monoxide (4×). The reaction vessel is pressurized with carbonmonoxide (100 psig, 690 KPa), sealed, and agitated at 100° C. for 4hours while the carbon monoxide pressure is maintained at 100 psig. Thereaction is cooled to ambient temperature and the carbon monoxide isvented from the reaction vessel. After filtration, the filtrate isconcentrated to a residue. The residue is partitioned between EtOAc (50mL) and water (50 mL). The organic phase is washed with brine (50 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure to aresidue. The residue is purified by flash chromatography to give4-hydroxymethyl-2-methyl-benzoic acid methyl ester as syrup (1.18 g,90%). LC-MS: 181.3 (M+1).

Step C

To a 0° C. solution of 4-hydroxymethyl-2-methyl-benzoic acid methylester (0.49 g, 2.7 mmol) in methylene chloride (8.0 mL) is added sodiumbicarbonate (0.46 g, 5.4 mmol) and Dess-Martin periodinane (0.14 g, 3.3mmol) sequentially. The reaction mixture is stirred at room temperaturefor 1.0 h and quenched with water (2.0 mL). The mixture is partitionedbetween CH₂Cl₂ (30 mL) and water (30 mL). The organic phase is washedwith brine (30 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure to a residue. The residue is purified by flashchromatography to give the title compound as syrup (0.35 g, 72%). ¹HNMR(CDCl₃) (ppm): 2.6 (3H, s), 3.85 (3H, s), 7.65-8.0 (3H, m), 10.0 (1H,s).

The title compound is prepared essentially as described in the synthesisof 4-formyl-2-methyl-benzoic acid methyl ester using the appropriatestarting material. Preparation 33A: 4-Formyl-2-trifluoromethyl-benzoicacid methyl ester (1.29 g, 92%), LC-ES/MS m/e 233.3 (M+1).

Preparation 34 4-Formyl-2-methyl-benzoic Acid Methyl Ester

To a IL Parr autoclave under N₂ atmosphere is charged palladium (II)acetate (2.19 g, 0.0097 mol) and butyl-1-diadamantylphosphine (10.42 g,0.291 mol) in toluene (100 mL). To this mixture are added(4-bromo-2-methyl-benzoic acid methyl ester (222 g, 0.969 mol),tetramethylethylenediamine (97.1 mL, 0.63 equiv), and toluene (325 mL).The autoclave is sealed and removed from N₂ atmosphere. To the autoclaveis placed a constant pressure of SynGas® (equal CO/H₂ mix, 75 psi). Thereaction is stirred for 18 h at 85° C. The crude reaction mixture isfiltered through a diatomaceous earth pad and washed with CH₂Cl₂ untilclear. The solvent is removed under reduced pressure to produce a redoil (86%) that crystallizes upon standing. ¹H NMR (400 MHz, CDCl₃) δ10.0 (s, 1H), 7.9 (d, 1H), 7.78 (m, 2H), 3.81 (s, 3H), 2.57 (s, 3H)

Preparation 35 2-Butoxy-4-formyl-benzoic Acid Methyl Ester Step A

To a 0° C. mixture of 2-hydroxy-4-methyl-benzoic acid methyl ester (1.0g, 6.0 mmol), triphenylphosphine (1.9 g, 7.2 mmol), and n-butanol (0.89g, 12.0 mmol) in THF (10.0 mL) is added DIAD (1.45 g, 7.2 mmol)dropwise. The mixture is stirred at room temperature overnight. Themixture is evaporated to dryness under reduced pressure. The residue ispartitioned between EtOAc (50 mL) and water (50 mL). The organic phaseis washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentratedunder reduced pressure to a residue. The residue is purified by flashchromatography to give 2-Butoxy-4-methyl-benzoic acid methyl ester as asyrup (1.0 g, 74%). LC-MS: 223.3 (M+1).

Step B

A mixture of 2-butoxy-4-methyl-benzoic acid methyl ester (0.85 g, 3.8mmol), dibenzoyl peroxide (100 mg), and NBS (0.68 g, 3.8 mmol) in CCl₄(20 mL) is heated to 70° C. overnight. The solid is filtered off and thefiltrate is concentrated to a residue. The residue is purified by flashchromatography to give 4-Bromomethyl-2-butoxy-benzoic acid methyl esteras a syrup (0.6 g, 52%). LC-MS: 301.0 (M+1).

Step C

A mixture of 4-bromomethyl-2-butoxy-benzoic acid methyl ester (0.0500 g,1.67 mmol), THF (10 mL), H₂O (10 mL), and LiOH (0.0160 g, 6.68 mmol) isstirred at 50° C. overnight. The mixture is acidified with 1.0 M HCl andthe product is extracted with EtOAc (40 mL). The organic phase is washedwith brine (20 mL) and dried (Na₂SO₄). After filtration, the filtrate isconcentrated under reduced pressure to a residue. The residue isdissolved in CH₂Cl₂ (10 mL) and MeOH (10 mL) and treated with 2.0 MTMSCHN₂ in hexane (5.0 mL, 10 mmol) at room temperature for 30 minutes.After concentration the residue is purified by flash chromatography ogive 2-Butoxy-4-hydroxymethyl-benzoic acid methyl ester as a syrup (270mg, 68%). LC-ES/MS: 239.3 (M+1).

Step D

To a 0° C. solution of 2-butoxy-4-hydroxymethyl-benzoic acid methylester (0.270 g, 1.13 mmol) in methylene chloride (10 mL) are addedsodium bicarbonate (0.14 g, 1.7 mmol) and Dess-Martin periodinane (0.58g, 1.4 mmol) sequentially. The reaction mixture is stirred at roomtemperature for 1.0 h and quenched with water (10 mL). The reactionmixture is partitioned between CH₂Cl₂ (30 mL) and water (20 mL). Theorganic phase is washed with brine (20 mL), dried (Na₂SO₄), filtered,and concentrated under reduced pressure to a residue. The residue ispurified by flash chromatography to give the title compound as a syrup(240 mg, 90%). LC-ES/MS: 237.3 (M+1).

Preparation 36[4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine Step A

To a suspension of 4-amino-3-methyl-phenol (10.8 g, 88 mmol) in THF (80mL) and sat. sodium bicarbonate (50 mL) is added benzyl chloroformate(18.0 g, 105 mmol) dropwise. The reaction mixture is stirred for 1.0 h.The two phases are separated and the organic phase is concentrated to aresidue. The residue is partitioned between EtOAc (100 mL) and 5% HCl(50 mL). The organic phase is washed with brine (100 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure to aresidue. The residue is purified by flash chromatography to give(4-Hydroxy-2-methyl)-carbamic acid benzyl ester as brown solid (21.0 g,93%). LC-ES/MS: 258.3 (M+1), 256.0 (M−1).

Step B

To a 0° C. solution of (4-hydroxy-2-methyl)-carbamic acid benzyl ester(21.0 g, 81.7 mmol) and imidazole (6.7 g, 98 mmol) in DMF (100 ml) isadded a solution of tert-butyldimethylsilyl chloride (14.8 g, 98 mmol)in DMF (20 mL). After the addition, the mixture is stirred at roomtemperature for 30 minutes. The solvent is removed under reducedpressure to give a residue, which is partitioned between EtOAc (100 mL)and 5% HCl (50 mL). The organic phase is washed with brine (100 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure to aresidue. The residue is purified by flash chromatography to give[4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-carbamic acidbenzyl ester as yellowish solid (28.8 g, 95%). LC-ES/MS: 372.3 (M+1).

Step C

To a 0° C. solution of[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-carbamic acidbenzyl ester (18 g, 48.5 mmol) in DMF (100 mL) is added sodium hydride(60% dispersion in oil, 2.3 g, 58 mmol) portionwise. The reactionmixture is stirred at room temperature for 30 minutes, followed by theaddition of iodomethane (8.2 g, 58 mmol). The mixture is stirred at roomtemperature overnight. The solvent is removed under reduced pressure togive a residue, which is partitioned between EtOAc (100 mL) and water(100 mL). The organic phase is washed with brine (100 mL), dried(Na₂SO₄), filtered, and concentrated under reduced pressure to aresidue. The residue is purified by flash chromatography to give[4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamicacid benzyl ester as oil (14.0 g, 75%). LC-ES/MS: 386.0 (M+1).

Step D

The mixture of[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamicacid benzyl ester (14.0 g, 36.0 mmol) and palladium on carbon (10 wt %,0.5 g) in methanol (100.0 mL) is stirred under a hydrogen atmosphere(balloon) at room temperature overnight. After filtration the filtrateis concentrated under reduced pressure to a residue. The residue ispurified by flash chromatography to give the title compound as oil (7.4g, 81%). LC-ES/MS: 252.3 (M+1).

Preparation 374-({[4-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl-2-methyl-benzoicAcid Methyl Ester

To a solution of[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine (0.64g, 2.6 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (0.38 g,2.1 mmol), acetic acid (0.25 g, 4.2 mmol) in 1,2-dichloroethane (10.0mL) is added sodium triacetoxyborohydride (0.89 g, 4.2 mmol) inportions. The mixture is stirred at room temperature overnight. Thereaction is quenched with 5% aq. sodium bicarbonate (5 mL) and ispartitioned between EtOAc (60 mL) and water (50 mL). The organic layeris washed with brine (50 mL), dried (Na₂SO₄), filtered, andconcentrated. The residue is purified by flash column chromatography toafford the title compound as a syrup (1.0 g, 95%). LC-ES/MS m/e 414.3(M+1).

Preparation 382-Butoxy-4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-benzoicAcid Methyl Ester

The title compound is prepared by reductive amination of[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine with2-butoxy-4-formyl-benzoic acid methyl ester, essentially as described inthe synthesis of4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoicacid methyl ester using the appropriate starting material. The titlecompound is obtained as syrup after workup. LC-ES/MS m/e 472.3 (M+1).

Preparation 394-{[(4-Hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-2-methyl-benzoicAcid Methyl Ester

To a solution of4-({[4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amino}-methyl)-2-methyl-benzoicacid methyl ester (1.0 g, 2.1 mmol) in THF (20.0 mL) is added 1.0 MTBAF/THF (3.2 mL, 3.2 mmol) at room temperature. The reaction mixture isstirred for 1.0 h. The reaction mixture is partitioned between EtOAc (30mL) and water (30 mL). The organic phase is washed with brine (30 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure to aresidue. The residue is purified by flash chromatography to give thetitle compound as oil (0.45 g, 62%). LC-ES/MS: 300.3 (M+1), 298.3 (M−1).

Preparation 402-Butoxy-4-{[(4-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-benzoicAcid Methyl Ester

The title compound (200 mg, 55%) is prepared essentially as described inthe synthesis of4-{[(4-hydroxy-2-methyl-phenyl)-methyl-amino]-methyl}-2-methyl-benzoicacid methyl ester using the appropriate starting material. LC-ES/MS:358.3 (M+1).

Preparation 413-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylicAcid Ethyl Ester

A mixture of 2-Azido-1,3-dichloro-benzene (25.0 g, 132.9 mmol) and4,4,4-trifluoro-but-2-ynoic acid ethyl ester (26.5 g, 159.6 mmol) intoluene (30 mL) are heated at 80° C. for 18 h. A large exotherm isobserved at 25 minutes. The reaction is removed from heat until exothermsubsides. Two regioisomers are observed in a range of 1:1 to 3:1 infavor of the desired product. The reaction mixture is concentrated underreduced pressure to 51 g of crude material and purified via columnchromatography using a gradient of 35-60% DCM in Hexanes to yield thetitle compound (28 g, 59%). ES/MS m/e 353.0 (M+1).

The following compound is prepared essentially according to thepreparation of3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester using the appropriate starting material.

Preparation 41A:3-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester (42%), ES/MS m/e 370.0 (M+1)

Preparation 42[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]methanol

To a 0° C. solution of3-(2,6-dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylicacid ethyl ester (28 g, 79 mmol) in THF (200 mL) is added dropwise 1MDIBAL (166 mL, 166 mmol) keeping the temperature below 5° C. After theaddition, the bath is removed and the reaction is stirred for 18 h. Thereaction is cooled to 0° C. and ether (300 mL) is added. The reaction isquenched with 1N HCl (250 mL) dropwise keeping the temperature below 15°C. The layers are separated and the water layer is washed with Ether(100 mL). The organics are combined and washed with water, brine, anddried with Na₂SO₄. The organic layer is concentrated to dryness to yieldthe title compound (24 g, 97%) and is used with no further purification.ES/MS m/e 312.0 (M+1).

The following compound is prepared essentially according to thepreparation of[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]methanolusing the appropriate starting material.

Preparation 42A:[3-(2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]methanol(95%), ES/MS m/e 328.0 (M+1).

Preparation 43 4-Iodo-3-trifluoromethyl-benzoic Acid

4-Amino-3-trifluoromethyl benzoic acid (1.8 g, 8.8 mmol) is suspended inconc. HCl (30 mL). A solution of sodium nitrite (0.76 g, 11.0 mmol) inwater (15 mL) is added dropwise at 0° C. The mixture is stirred at 0-10°C. for 30 min. A solution of potassium iodide (14.6 g, 88 mmol) in water(25 mL) is added dropwise. The mixture is stirred at room temperaturefor 1 h. The product is extracted with EtOAc (80 mL), washed with brine(80 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure to a residue. The residue is purified by flash chromatographyusing a gradient (EtOAc/Hexane) to afford the title compound (2.4 g,86%) as a solid. LC-ES/MS m/e 339.3 (M+23), 315.0 (M−1).

Preparation 44 6-Bromo-benzo[d]isothiazole-3-carboxylic Acid

The title compound is prepared essentially according to Procedure 3 inWO 2005/092890. ES/MS m/e 255.0 (M−1).

Preparation 456-(4-Hydroxy-2-methyl-phenyl)-benzo[d]isothiazole-3-carboxylic Acid

To a degassed solution of 6-Bromo-benzo[d]isothiazole-3-carboxylic acid(0.42 g, 1.54 mmol),3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-phenol (0.54,2.31 mmol), 2-Dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.064g, 0.154 mmol), and potassium phosphate (0.71 g, 3.1 mmol) in dioxane (8mL) and water (4 mL) is added Pd(OAc)₂ (6.5 mg, 0.03 mmol). The reactionis degassed again and heated to 80 degrees for 18 h. The reaction iscooled to room temperature and concentrated under reduced pressure. Thematerial is diluted with EtOAc and 1N HCl. The layers are separated andconcentrated under reduced pressure. The crude material is diluted with20 mL of MeOH and 2 mL H₂SO₄ and heated to reflux for 2 h. The reactionis concentrated onto silica and purified using a gradient of 20 to 50%EtOAc in Hexanes to yield the title compound (0.12 g, 26% yield). ES/MSm/e 300.0 (M+1).

Preparation 46 6-Bromo-1H-indazole-3-carboxylic Acid Methyl Ester

The title compound is prepared from 6-Bromo-1H-indole-2,3-dioneessentially as described in procedure 4 of WO2005092890. ES/MS m/e 254.0(M+1)

Preparation 47 6-Bromo-1-isopropyl-1H-indazole-3-carboxylic Acid MethylEster

The title compound is prepared essentially as described in procedure 1dWO2005/080389 substituting 6-Bromo-1H-indazole-3-carboxylic acid methylester for 1H-indazole-3-carboxylic acid methyl ester. ES/MS m/e 296.0(M+1)

Preparation 48 6-Bromo-1-methyl-1H-indazole-3-carboxylic Acid MethylEster

The title compound is prepared essentially as described in the synthesisof 6-bromo-1-isopropyl-1H-indazole-3-carboxylic acid substituting6-bromo-1H-indazole-3-carboxylic acid methyl ester for1H-indazole-3-carboxylic acid methyl ester and methyl iodide forisopropyl iodide ES/MS m/e 268.0 (M+1).

Preparation 496-(4-Hydroxy-2-methyl-phenyl)-1-methyl-1H-indazole-3-carboxylic Acid

To a degassed solution of 6-bromo-1-methyl-1H-indazole-3-carboxylic acidmethyl ester (0.61 g, 2.4 mmol),3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-phenol (0.84,3.6 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.098g, 0.240 mmol), and potassium phosphate (1.0 g, 4.8 mmol) in dioxane (10mL) and water (5 mL) is degassed and treated with Pd(OAc)₂ (27 mg, 0.12mmol). The reaction is degassed again and heated to 90° C. for 18 h. Thereaction is cooled to room temperature, concentrated onto silica gelunder reduced pressure, and purified via flash chromatography using agradient of 10% to 30% EtOAc in Hexanes to yield the title compound(0.53 g, 75%). ES/MS m/e 297.0 (M+1).

Preparation 506-(4-Hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indazole-3-carboxylic AcidMethyl Ester

The title compound (2.88 g, 98%) is prepared essentially according tothe synthesis of6-(4-hydroxy-2-methyl-phenyl)-1-methyl-1H-indazole-3-carboxylic acidexcept using a gradient of 20% to 60% EtOAc in Hexanes in the finalpurification. ES/MS m/e 325.0 (M+1).

Preparation 51 4-Amino-3-fluoro-phenol

A mixture of 3-fluoro-4-nitrophenol (2.20 g, 14.0 mmol) in 25 mL ethylacetate is evacuated under reduced pressure and filled with nitrogenthree times. Palladium, 10% by weight on carbon (220 mg) is added. Themixture is evacuated under reduced pressure and filled with nitrogenthree times. The mixture is evacuated under reduced pressure and filledwith hydrogen. The mixture is stirred under hydrogen atmosphere(balloon) over night. The mixture is then filtered over diatomaceousearth and concentrated to provide the title compound (1.7 g, 96%) as abrown solid. ¹H NMR (400 MHz, DMF-d₇) δ 8.75 (s, 1H), 6.78 (m, 1H), 6.40(m, 1H), 6.50 (m, 1H), 4.38 (s, 2H).

Preparation 524-[(2-Fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic Acid MethylEster

A mixture of 4-amino-3-fluoro-phenol (900 mg, 7.08 mmol) and4-formyl-2-methyl-benzoic acid methyl ester (1.23 g, 6.90 mmol) in 35 mLacetic acid is stirred for two hours at room temperature. Sodiumtriacetoxyborohydride (3.20 g, 15.1 mmol) is added and stirred at roomtemperature. Upon completion, the mixture is concentrated under reducedpressure and partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The aqueous layer is separated and extracted withethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO₄)and concentrated under reduced pressure. The residue is purified on 120g silica eluting with a gradient of ethyl acetate in heptane (10% to60%) to provide the title compound (1.9 g, 93%) as a yellow oil. ES/MSm/e 290.0 (M+1).

Preparation 534-{[(2-Fluoro-4-hydroxy-phenyl)-methyl-amino]-methyl}-2-methyl-benzoicAcid Methyl Ester

A mixture of4-[(2-fluoro-4-hydroxy-phenylamino)-methyl]-2-methyl-benzoic acid methylester (1.89 g, 6.53 mmol) and 37% formaldehyde (2.0 mL) in acetic acid(20 mL) is stirred for 40 minutes. Sodium triacetoxyborohydride (2.80 g,13.2 mmol) is added and stirred at room temperature. Upon completion ofthe reaction, the mixture is concentrated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The aqueous layer isseparated and extracted with ethyl acetate (3×). The combined ethylacetate layers are dried (MgSO₄) and concentrated under reducedpressure. The residue is purified on 120 g silica eluting with agradient of ethyl acetate in heptane (10% to 60%) to provide the titledcompound (1.0 g, 51%) as a white solid. LC-ES/MS m/e 304.0 (M+1).

Preparation 54 Ethyl4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate

To a 2° C. suspension of (carbethoxymethyl) triphenylphosphonium bromide(1000 g, 2.28 mol) in 5 L of THF under nitrogen is added triethylamine(642 mL, 4.57 mol). After the mixture is stirred for 30 minutes at 2°C., trifluoroacetic acid anhydride (357 mL, 2.51 mol) is added viaaddition funnel over 40 minutes. The mixture is allowed to stir for 2hours and the precipitate is filtered off. The filtrate liquids areconcentrated under reduced pressure to afford a yellow oily residue. Theresidue is triturated with water (3 L) to afford a crystalline solidthat is collected by filtration. The solid is washed with water anddried under vacuum overnight. The solid is recyrstallized fromMeOH-water to give the title compound as a white solid (770 g, 76%).ES/MS m/e 446 (M+1)

Preparation 55 4,4,4-Trifluoro-2-butynoic Acid Ethyl Ester

A mixture of ethyl4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate (270 g, 617mmol) and potassium carbonate (54 g, 490 mmol) is heated from 160° C. to225° C. in 3 h at 2-3 mbar vacuum. The title compound is distilled andrecovered in a cold trap to yield the title compound (85 g, 83%) as aslightly yellow oil. ES/MS m/e 167 (M+1)

Preparation 56 4-Bromo-2-methylbenzoic Acid Methyl Ester

Acetyl chloride (199 mL, 2.79 mol) is added to a solution of4-bromo-2-methylbenzoic acid (500 g, 2.32 mol) in methanol (2500 mL) at5° C. The mixture is theated at 65° C. for 7 hours. The mixture iscooled to room temperature and sodium carbonate (19 g, 0.18 mol) isadded. The reaction mixture is stirred for 15 minutes. The slurry isfiltered and the filtrate is concentrated under reduced pressure. Theresulting residue is partitioned between MTBE (400 mL) and water (400mL). The organic phase is washed with brine, dried over magnesiumsulfate, and concentrated to give the title compound (520 g) as a goldenoil. ES/MS m/e 216 (M+1)

Preparation 57 4-formyl-2-methyl-benzoic Acid, Methyl Ester

A mixture of 4-bromo-2-methylbenzoic acid methyl ester (513 g, 2.24mol), tetramethylethylenediamine (209 mL, 1.39 mol), palladium acetate(5 g), cataCXium A® (23 g) and toluene (3000 mL) is charged into areactor. The reactor is pressurized with SynGas® (100 psi). The mixtureis heated to 85° C. and held under SynGas® (100 psi) overnight. After 18h, the reaction is cooled to room temperature, filtered through a pad ofdiamtomaceous earth, and concentrated to an oil. The residue istriturated with heptane to afford the title compound as a yellow solidthat is filtered and washed with heptane (350 g, 88% yield). ES/MS m/e179 (M+1)

Preparation 58 4-((4-Hydroxy-2-methylphenylamino)methyl)-2-methylBenzoic Acid, Methyl Ester

4-Amino-m-cresol (242 g, 1.96 mol) is added to a slurry of4-formyl-2-methyl-benzoic acid, methyl ester (350 g, 1.96 mol) andacetic acid (3100 mL) at room temperature. Sodium triacetoxyborohydride(728 g, 3.44 mol) is added portionwise, keeping the temperature below30° C. using an ice water bath. After overnight stirring, the reactionmixture is concentrated under reduced pressure. The residue is adjustedto pH 5 using aqueous saturated sodium bicarbonate. The resulting solidis filtered off, washed with water, and dried under vacuum overnight togive the title compound (460 g, 82%) as a brown powder. ES/MS m/e 179(M+1)

Preparation 594-{[(4-hydroxy-2-methylphenyl)methylamino]methyl}-2-methyl Benzoic Acid,Methyl Ester

Formic acid (165 mL, 4.37 ml) is added dropwise to a slurry of4-((4-hydroxy-2-methylphenylamino)methyl)-2-methyl benzoic acid methylester (250 g, 0.88 mol) and formaldehyde (435 mL, 37% in aqueous) atroom temperature. The reaction is stirred overnight. To the reactionmixture is added 1M HCl (600 mL) and the mixture is extracted with MTBE.The aqueous phase is adjusted to pH 8 with 6M NaOH and extracted withMTBE (2×1000 mL). The combined organic layers are combined, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue is purified using a plug of silica gel eluting with 10%EtOAc/hexanes to give the title compound (127 g, 48%) as a white solid.ES/MS m/e 300 (M+1)

Preparation 605-Bromomethyl-1-(2,6-dichlorophenyl)-4-trifluoromethyl-1H-[1,2,3]-triazole

Triphenylphosphine (16.4 g, 62.5 mmol) is added to a suspension of[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-yl]-methanol(13 g, 41.69 mmol) in dichlormethane (80 mL). The mixture is cooled to0° C. and carbon tetrabromide (20.7 g, 62.5 mmol) is added. The reactionis stirred at room temperature for 1.5 hours. The solvent is evaporatedunder reduced pressure and the residue is purified by flashchromatography eluting with hexanes/EtOAc (95:5 to 8:2) to obtain thetitle compound (15.6 g, 96% yield). ES/MS m/e 374 (M+1)

Examples Example 1

4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylicAcid Step A

To a solution of5-chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole(0.1 g, 0.328 mmol) in dimethylformamide (3 mL) is added4′-hydroxy-2′methyl-biphenyl-4-carboxylic acid methyl ester (0.079 g,0.326 mmol) and cesium carbonate (0.21 g, 0.646 mmol). The reaction isheated to 55° C. for 2.5 h and is cooled to room temperature. Thereaction mixture is concentrated under reduced pressure. The residue isdissolved in 1N hydrochloric acid and ethyl acetate. The layers areseparated and the aqueous is extracted again with ethyl acetate. Theorganic layers are combined and are washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to give4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylicacid methyl ester. ES/MS m/e (³⁵Cl/³⁷Cl) 510.2/512.2 (M+1).

Step B

A solution of4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylicacid methyl ester (4.55 g, 1 equiv) and 1N NaOH (44.6 mL, 5 equiv) inMeOH (200 mL) is heated to 75° C. for 1 h. The reaction mixture iscooled to room temperature and is concentrated under reduced pressure.The residue is dissolved in water (200 mL) and the solution is acidifiedwith 5N HCl. The resulting precipitate is filtered and dried underreduced pressure to give the title compound (4.21 g, 95%). ES/MS m/e(³⁵Cl/³⁷Cl) 496.3/498 (M+1).

The following compounds in Table 1 are prepared essentially according tothe preparation of4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylicacid using the appropriate starting material.

TABLE 1 Ex Name Physical Data 22-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-phenyl}-benzo[b]thiophene-6- 538 (M + 1)carboxylic acid 3 4′-[5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H-LC-ES/MS m/e [1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4- 496(M + 1) carboxylic acid 42′-Chloro-4′-[5-isopropyl-3-(2-trifluoromethyl-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid 516 (M + 1) 54-[({4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)- 551 (M + 1);methyl]-2-methyl-benzoic acid 549 (M − 1) 73-(2-{4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-vinyl)- 506.0 (M + 1),benzoic acid 8 3-(2-{4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-LC-ES/MS m/e [1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-vinyl)- 538.0(M + 1), benzoic acid 93-(2-{4-[5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H- LC-LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-vinyl)- m/e benzoic acid522.2 (M + 1) 10 5-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-MS:[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2- 502 (M + 1),100% carboxylic acid 11 5-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-LC-ES/MS m/e [1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2-502 (M + 1) carboxylic acid

Example 12

3-(2-(4-(3-(2,6-Dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoicAcid Step A

To a solution of 3-(2-(4-hydroxy-2-methyl-phenyl)-vinyl)-benzoic acidmethyl ester (0.09 4 g, 0.351 mmol) and(3-(2,6-dichloro-phenyl)-5-isopropyl-3H-(1,2,3)triazol-4-yl)-methanol(0.100 g, 0.351 mmol) in THF (3 mL) are added triphenylphosphine (0.184g, 0.702 mmol) and diethyl azodicarboxylate (0.120 g, 0.720 mmol). Thereaction is stirred overnight. The reaction is partitioned between etherand water. The organic layer is washed with brine and dried over sodiumsulfate. The organic layers are filtered and concentrated. The crudesolid is purified via flash chromatography using hexane:ethyl acetate(2:1) as eluent to give3-(2-(4-(3-(2,6-Dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoicacid methyl ester (0.04 g). ES/MS m/e (³⁵Cl/³⁷Cl) 535.8/538.2 (M+1).

Step B

To a solution of3-(2-(4-(3-(2,6-dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoicacid methyl ester (0.025 g, 0.046 mmol) in THF (3 mL) is added lithiumhydroxide (0.005 g, 0.21 mmol). The reaction mixture is heated to 55° C.The reaction is determined to be incomplete due to the presence ofstarting material by TLC (1:1 hexane/ethyl acetate). An additionalamount of lithium hydroxide (0.050 g) is added and the reaction isheated to 60° C. for 3 h. The reaction is quenched with aqueous 1 N HCland is extracted with ethyl acetate. The organic layer is washed withbrine, dried over sodium sulfate, filtered, and concentrated to give thetitle compound. ES/MS m/e 521.8 (M+1)

The following compounds in Table 2 are prepared essentially according tothe preparation of3-(2-(4-(3-(2,6-dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoicacid using the appropriate starting material.

TABLE 2 Physical Ex Name Data 134-[({4-[5-Isopropyl-3-(2,6-dichloro-phenyl)-3H- ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 553 (M + 1)amino)-methyl]-2-methyl-benzoic acid 146-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H-indole-3-carboxylic m/e acid548.3 (M + 1) 156-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-2- m/e carboxylic acid567.0 (M + 1) 16 6-{4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-LC-ES/MS [1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- m/ebenzo[b]thiophene-3-carboxylic acid 568.0 (M + 1) 176-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl- m/e1H-indole-3-carboxylic acid 576.8 (M + 1) 186-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H- m/eindole-3-carboxylic acid 547.0 (M) 196-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- m/ebenzo[b]thiophene-3-carboxylic acid 550.0 (M) 206-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- m/ebenzo[b]thiophene-3-carboxylic acid 566.0 (M + 1) 216-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl- m/e1H-indole-3-carboxylic acid 603.0 (M + 1) 226-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- m/ebenzo[d]isothiazole-3-carboxylic acid 549.0 (M − 1) 236-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H- m/eindazole-3-carboxylic acid 546.0 (M − 1) 246-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H- m/eindazole-3-carboxylic acid 574.0 (M − 1) 256-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-1H- m/eindazole-3-carboxylic acid 562.0 (M − 1) 266-{4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl- m/e1H-indazole-3-carboxylic acid 590.0 (M − 1) 276-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl- m/e1H-indazole-3-carboxylic acid 574.0 (M − 1) 284′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4- MS/APCIylmethoxy]-3′-methyl-biphenyl-4-carboxylic acid m/e 496 (M + 1) 292′-Chloro-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid m/e 516 (M + 1)30 4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4- MS/APCIylmethoxy]-2′-fluoro-biphenyl-4-carboxylic acid m/e 500 (M + 1) 314′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4- MS/APCIylmethoxy]-2′-trifluoromethyl-biphenyl-4-carboxylic acid m/e 550 (M + 1)32 4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4- MS/APCIylmethoxy]-2′-nitro-biphenyl-4-carboxylic acid m/e 527 (M + 1) 332′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H- MS/APCI[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid m/e 560 (M + 1)34 4′-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic m/e acid480.0 (M + 1) 352′-Chloro-4′-[3-(2-chloro-6-fluoro-phenyl)-5-isopropyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid m/e 500.0 (M + 1)36 4′-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic m/e acid512.0 (M + 1) 372′-Chloro-4′-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylic acid m/e 532.0 (M + 1)38 3-[({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 539.2 (M + 1) 393-[({4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 555.0 (M + 1) 403-[({4-[5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 539.2 (M + 1) 414-[({4-[5-Isopropyl-3-(2-trifluoromethyl-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 539.2 (M + 1) 424-[({4-[5-Isopropyl-3-(2,6-Dichloro-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 539.0 (M + 1) 436-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3- m/e carboxylic acid552.0 (M + 1) 44 3-[({4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H-LC-ES/MS [1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 523.0 (M + 1) 453-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid m/e 523.3 (M − 1) 464-[({4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 549.0 (M − 2),amino)-methyl]-2-methyl-benzoic acid 551.0 (M − 0) 472-Butoxy-4-[({4-{3-(2,6-dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- m/eamino)-methyl]-benzoic acid 611.3 (M + 1), 609.3 (M − 1) 485-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-phenyl}-thiophene-2-carboxylic acid m/e 488 (M + 1), 95.8%49 5-{4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2- m/e carboxylicacid 518 (M + 1), 92.3% 505-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-phenyl}-thiophene-2-carboxylic acid m/e 488 (M + 1) 515-{4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-thiophene-2- m/e carboxylicacid 518 (M + 1) 52 4-[({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-LC-ES/MS [1,2,3]triazol-4-ylmethoxy]-2-fluoro-phenyl}-methyl-amino)- m/emethyl]-2-methyl-benzoic acid. 557.0 (M + 1) 534′-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic m/e acid508.0 (M − 1) 544′-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol- LC-ES/MS4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic acid m/e 492.0 (M − 1) 554′-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic m/e acid520.0 (M − 1)

Example 56

3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoicAcid Step A

To a room temperature solution of1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanol(70 mg, 0.167 mmol) in toluene (2 mL) are added 3-mercapto-benzoic acidmethyl ester (28 mg, 0.167 mmol) and tri-N-butylphosphine (62 μL, 0.251mmol). The reaction mixture is cooled to 0° C. To the reaction mixtureis added 1,1′-(azocarbonyl)-dipiperidine (63 mg, 0.251 mmol). Thereaction mixture is warmed to room temperature and stirred overnight.The reaction mixture is concentrated and the residue is chromatographed(40 g SiO₂, 0% to 30% EtOAc/Hexanes) to yield3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoicacid methyl ester (62 mg, 65%).

Step B

To an ambient temperature solution of3-(1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoicacid methyl ester (53 mg, 0.0934 mmol) in dioxane (2 mL) is added asolution of lithium hydroxide (140 μL, 0.280 mmol, 2.0N in water). Thereaction is heated to 50° C. for 2 h. The reaction mixture isconcentrated and the residue is diluted with Et₂O and water. The aqueouslayer is adjusted to pH ˜4 and is extracted with a second portion ofEt₂O. The combined organic layers are washed with water, dried (MgSO₄),filtered, and concentrated to yield the title compound (49 mg, 94%).LC-ES/MS m/e 556.3 (M+1), HPLC purity: 100%

The following compounds in Table 3 are prepared essentially according tothe preparation of3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethylsulfanyl)-benzoicacid using the appropriate starting material.

TABLE 3¹ Ex Name Physical Data 574-(2-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-phenyl}-propoxy)-benzoic acid 540.0 (M + 1),100.0% 58 3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- Isomer 1[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- LC-ES/MS m/eethylsulfanyl)-benzoic acid 556.3 (M + 1) 593-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- Isomer 2[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- LC-ES/MS m/eethylsulfanyl)-benzoic acid 556.3 (M + 1) 603-(1-{4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H- Isomer 1[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethoxy)- LC-ES/MS m/ebenzoic acid 523.0 (M + 1) 613-(1-{4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H- Isomer 2[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethoxy)- LC-ES/MS m/ebenzoic acid 523.0 (M + 1) 62[3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethoxy)- 554.0 (M + 1)phenyl]-acetic acid 633-[3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethoxy)- 568.0 (M + 1)phenyl]-propionic acid 643-[({4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 563.0 (M − 1)amino)methyl]-benzoic acid 653[({4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 551.0 (M − 1)amino)-methyl]-benzoic acid 664-[({4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 631.0 (M − 1)amino)-methyl]-2-trifluoromethyl-benzoic acid 674-[({4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 619.0 (M − 1)amino)-methyl]-2-trifluoromethyl-benzoic acid 684-[({4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 621.0 (M − 1)amino)-methyl]-2-trifluoromethyl-benzoic acid 694-[({4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 603.0 (M − 1)amino)-methyl]-2-trifluoromethyl-benzoic acid 704-[({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl- 605.0 (M − 1)amino)-methyl]-2-trifluoromethyl-benzoic acid 716-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}- 577.0 (M − 1)benzo[d]isothiazole-3-carboxylic acid 724-[({4-[5-Cyclopropyl-3-(2-trifluoromethoxy-phenyl)-3H- LC-ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-565.0 (M − 1) 2-methyl-benzoic acid ¹When present, individualenantiomers are isolated from the racemic mixture via chiralchromatography. Isomer 1 elutes from the column first and isomer 2elutes from the column second.

Example 73

4-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoicAcid Step A

To an ambient temperature solution of2-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-propan-2-ol(100 mg, 0.230 mmol) in DCE (1 mL) is added zinc iodide (37 mg, 0.115mmol). The reaction is stirred at room temperature for 10 min. Asolution of methyl 4-mercaptobenzoate (38 mg, 0.225 mmol) in DCE (1 mL)is added and the reaction is stirred overnight at room temperature. Thereaction is concentrated under reduced pressure and the residue ischromatographed (SiO₂ 40 g, 0% to 30% EtOAC/Hexane to yield4-(1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoicacid methyl ester (114 mg, 87%). ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, 2H,J=7.9 Hz), 7.52-7.39 (m, 3H), 7.22 (s, 1H), 7.16 (d, 2H, J=7.8 Hz), 7.11(d, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.4 Hz), 4.90 (s, 2H), 3.90 (s, 3H),3.23 (sept, 1H, J=6.6 Hz), 2.01 (s, 3H), 1.64 (s, 6H), 1.46 (d, 6H,J=6.6 Hz).

Step B

To an ambient temperature solution of3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoicacid methyl ester (110 mg, 0.188 mmol) in dioxane (2 mL) is added asolution of lithium hydroxide (282 μL, 0.564 mmol, 2.0N in water). Thereaction is heated to 50° C. for 2 h. The reaction is concentrated andthe residue is diluted with Et₂O and water. The aqueous layer isadjusted to pH ˜4 and extracted with a second portion of Et₂O. Thecombined organic layers are washed with water, dried (MgSO₄), filtered,and concentrated to yield the title compound (106 mg, 99%). LC/MS (ES+):570.0, 100.0%

The following compounds in Table 4 are prepared essentially according tothe preparation of4-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoicacid using the appropriate starting material.

TABLE 4 Ex Name Physical Data 743-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-phenyl}-1-methyl- 556.0,ethylsulfanyl)-benzoic acid 754-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-phenyl}-1-methyl- 556.0,ethylsulfanyl)-benzoic acid 76[3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-phenyl}-1-methyl- 570.0,ethylsulfanyl)-phenyl]-acetic acid 77[4-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-phenyl}-1-methyl- 570.0,ethylsulfanyl)-phenyl]-acetic acid 783-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1- 570.0methyl-ethylsulfanyl)-benzoic acid 794-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1- 570.0,methyl-ethylsulfanyl)-benzoic acid 80[3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1- 584.0,methyl-ethylsulfanyl)-phenyl]-acetic acid 81[4-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1- 584.0,methyl-ethylsulfanyl)-phenyl]-acetic acid 823-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-1- 570.0,methyl-ethylsulfanyl)-benzoic acid 834-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-1- 570.0,methyl-ethylsulfanyl)-benzoic acid 84[3-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-1- 584.0,methyl-ethylsulfanyl)-phenyl]-acetic acid 85[4-(1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- LC/MS (ES+):[1,2,3]triazol-4-ylmethoxy]-3-methyl-phenyl}-1- 584.0,methyl-ethylsulfanyl)-phenyl]-acetic acid

Example 86

2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylicAcid Isobutyl-Amide Step A

To thionyl chloride (1.5 mL, 20 mmol) is added2′-bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylicacid (0.074 g, 0.13 mmol). The reaction is stirred overnight at roomtemperature. The reaction mixture is concentrated under reduced pressureto give2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonylchloride.

Step B

To2′-bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonylchloride (0.043 mmol) in dichloromethane (2 mL) is added s-butyl amine(0.05 mL, 0.5 mmol). The reaction is stirred at room temperature for 1 hand concentrated under reduced pressure. The residue is slurried in 1 Nhydrochloric acid, and the solid is filtered to give the title compound(0.011 g). ES/MS m/e 617.0 (M+1).

The following compounds in Table 5 are prepared essentially according tothe preparation of2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carboxylicacid isobutyl-amide using the appropriate starting material.

TABLE 5 Ex Chemical Name Physical Data 872′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5- MS/ES m/eisopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl- 589.0 (M + 1)4-carboxylic acid ethylamide 88 2′-Bromo-4′-[3-(2,6-dichloro-phenyl)-5-MS/ES m/e isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl- 574.8(M + 1) 4-carboxylic acid methylamide 894′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H- ES/MS m/e[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl- (³⁵Cl) 4-carboxylic acidethylamide 523.0 (M + 1)

Example 90

4′-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4Carboxylic Acid Amide

To a solution of4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-biphenyl-4-carbonitrile(0.150 mg) in dimethyl sulfoxide (1.2 mL) is added potassium carbonate(0.03 g) and 50% aqueous hydrogen peroxide (0.2 mL). The reactionmixture is allowed to stir at room temperature for 30 minutes. Thereaction mixture is diluted with water (55 mL), cooled to 0° C., andfiltered. The resulting solids are washed with cold (−78° C.) hexanes.The white solids are allowed to dry under reduced pressure to give thetitle compound (0.100 g, 64%). ¹H NMR (300 MHz, CDCl₃) δ 7.9 (d, 2H),7.6 (d, 2H), 7.5 (m, 5H), 6.9 (d, 2H), 5.0 (s, 2H), 3.3 (p, 1H), 1.5 (d,6H);′ APCI/MS m/e 481 (M+1), HPLC purity 98.5%.

Example 91

4-(Benzyl-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-amino)-benzoicAcid Step A

To a 0° C. solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(309 mg, 1.08 mmol), 4-(4-hydroxy-2-methyl-benzylamino)-benzoic acidmethyl ester (292 mg, 1.08 mmol), and tri-n-butylphosphine (344 mg, 1.70mmol) in toluene (50 mL) is added 1,1′-(Azodicarbonyl)-dipiperidine (450mg, 1.78 mmol). The reaction mixture is stirred for 1.5 h. The reactionmixture is diluted with heptane, filtered, and concentrated underreduced pressure. The residue is purified by flash chromatography (40 gsilica, gradient EtOAc/Hexane) to give4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoicacid methyl ester (309 mg, 1.08 mmol). MS: 539.0 (M+1).

Step B

A solution of4-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoicacid methyl ester (90 mg, 0.17 mmol) and benzaldehyde (28 mg, 0.26 mmol)is stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) is added to the reaction mixture andstirred over night. The reaction mixture is concentrated under reducedpressure and partitioned between ethyl acetate and saturated sodiumbicarbonate. The layers are separated and the aqueous layer is extractedwith ethyl acetate (2×). The combined ethyl acetate layers are dried(MgSO₄) and concentrated under reduced pressure. The residue is purifiedby flash chromatography on 12 g silica with ethyl acetate in heptanegradient to provide4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoicacid methyl ester (32 mg, 30%). MS: 629.0 (M+1). LC-MS: 613.3 (M−1).

Example 92

3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy}-2-methyl-benzyl]-methyl-amino)-benzoicAcid Step A

To a mixture of3-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoicacid ethyl ester (160 mg, 0.29 mmol) and sodium hydride (13 mg, 0.33mmol) in anhydrous N,N-dimethyl formamide is added iodomethane (50 mg,0.35 mmol). After three hours, more iodomethane (50 mg, 0.35 mmol) isadded and the mixture is heated to 60° C. After three hours, moreiodomethane (50 mg, 0.35 mmol) is added and the mixture is stirred atroom temperature over night. The mixture is then partitioned betweendiethylether and water. The aqueous layer is extracted three times withdiethylether. The combined ether layers are dried (MgSO4) andconcentrated under reduced pressure. The crude residue is purified on 12g of silica with ethyl acetate in heptane gradient to provide3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoicacid ethyl ester (20 mg, 12%) LC-MS: 567.0 (M+1).

Step B

To a solution of3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoicacid ethyl ester (20 mg, 0.035 mmol) in THF (4.0 mL) and methanol (4.0mL) is added 5 M NaOH (0.5 mL). The reaction mixture is heated to 70° C.for two hours and cooled to room temperature. A solution of 5 M HCl (0.5mL) is added. The reaction mixture is concentrated and triturated withmethanol and then water is added to precipitate the product. The titlecompound (10 mg, 53%) is collected by vacuum filtration as a whitesolid. LC-MS: 537.3 (M−1)

Example 93

4-[({6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoicAcid Step A

To an ambient temperature solution of[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol(2.0 g, 6.64 mmol) in degassed toluene (22 mL) are added6-chloro-2-methyl-3-nitro-pyridine (1.15 g, 6.64 mmol), cesium carbonate(3.25 g, 9.96 mmol), 2-(di-t-butylphosphino)-1,1′-binapthyl (332 mg,0.833 mmol, 12.5 mol %), and palladium (II) acetate (150 mg, 0.666 mmol,10 mol %). The reaction mixture is heated to 70° C. overnight. Thereaction is filtered through a pad of diatomaceous earth. The filtrateis concentrated and the residue is chromatographed (SiO₂ 120 g, 0% to20% EtOAc/Hexane to yield6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-3-nitro-pyridine(2.78 g, 96%). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, 1H, J=8.8 Hz),7.61-7.53 (m, 2H), 7.48-7.42 (m, 2H), 6.51 (d, 1H, J=8.8 Hz), 5.42 (s,2H), 3.26 (sept, 1H, J=7.0 Hz), 2.71 (s, 3H), 1.43 (d, 6H, J=7.0 Hz).

Step B

To a room temperature solution of6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-3-nitro-pyridine(2.78 g, 6.35 mmol) in EtOH/THF (1/1, 200 mL) is added platinum (II)oxide (144 mg, 0.636 mmol, 10 mol %). The mixture is stirred under anatmosphere of hydrogen gas. After 3 h, the reaction is filtered throughdiatomaceous earth. The filtrate is concentrated and the residue ischromatographed (SiO₂ 120 g, 0% to 30% EtOAc/Hexane to yield6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-ylamine(2.28 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.51 (m, 2H), 7.46-7.38(m, 2H), 6.92 (d, 1H, J=8.4 Hz), 6.26 (d, 1H, J=8.4 Hz), 5.25 (s, 2H),3.29 (sept, 1H, J=7.0 Hz), 2.24 (s, 3H), 1.40 (d, 6H, J=7.0 Hz).

Step C

To a room temperature solution of6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-ylamine(150 mg, 0.369 mmol) in MeOH (6 mL) is added 4-formyl-2-methyl-benzoicacid methyl ester (72 mg, 0.406 mmol), and the mixture is stirred for 10min. Decaborane (14 mg, 0.0738 mmol) is added. After 2 h, formaldehyde(2.0 mL, 37 wt % in water) is added and the reaction is stirred for 10minutes. A second portion of decaborane (14 mg, 0.0738 mmol) is added.After 2 h, the reaction is concentrated and the residue ischromatographed (SiO₂ 40 g, 0% to 20% EtOAc/Hexane to yield4-[({6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoicacid methyl ester (156 mg, 73%). ¹H NMR (400 MHz, DMSO) δ 7.77-7.72 (m,1H), 7.70 (d, 2H, J=7.9 Hz), 7.66-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.46(d, 1H, J=8.8 Hz), 7.23-7.19 (m, 2H), 6.37 (d, 1H, J=8.4 Hz), 5.27 (s,2H), 3.95 (s, 2H), 3.79 (s, 3H), 3.28 (sept, 1H, J=6.6 Hz), 2.47 (s,6H), 2.32 (s, 3H), 1.28 (d, 6H, J=6.6 Hz).

Step D

A solution of4-[({6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoicacid methyl ester (147 mg, 0.251 mmol) in dioxane (2 mL) is treated witha solution of lithium hydroxide (378 mL, 0.756 mmol, 2.0N in water) andheated to 50° C. After 2 h, the reaction is concentrated and the residueis partitioned between Et₂O and water. The aqueous layer is adjusted topH ˜7 and is extracted with a second portion of Et₂O. The combinedorganic layers are washed with water, dried (MgSO₄), filtered, andconcentrated to yield the title compound (138 mg, 97%). LC/MS (ES+):570.0, 100%.

Example 94

3-(2-{2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoicAcid Step A

To solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(0.100 g, 1 eq) and 2-chloro-4-fluorobenzaldehyde (0.11 g, 2 eq) indimethylformamide (3 mL) is added cesium carbonate (0.23 g, 2 eq). Thereaction is heated to 100° C. overnight. The reaction is cooled to roomtemperature and water is added. The mixture is extracted with ethylacetate and the organic layers are washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residueis purified via flash chromatography eluting with 0-10% ethylacetate:toluene to give 0.101 g of2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde.ES/MS m/e 426.1 (M+1)

Step B

To triethyl phosphate (0.75 mL, 1 eq) is added methyl4-(bromomethyl)benzoate (1.0 g, 1 eq). The reaction is heated to 100° C.overnight. The reaction mixture is purified via flash chromatographyeluting with a step gradient of 0% to 5% to 10% methylalcohol:chloroform to give 3-(Diethoxy-pThosphorylmethyl)-benzoic acidmethyl ester (0.763 g).

Step C

To a 0° C. solution of 3-(diethoxy-phosphorylmethyl)-benzoic acid methylester (1.2 g, 4 eq) in diethyl ether (15 mL) is added sodium hydride(0.17 g, 4 eq). After 1 h,2-chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde(0.44 g, 1 eq) in diethyl ether (5 mL) is added and the reaction isstirred overnight. Upon completion, the reaction is quenched with water.The aqueous solution is acidified with 1N HCl and extracted two timeswith ethyl acetate. The organic layers are combined, washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue is purified via filter chromatography eluting with10% ethyl acetate:toluene to give3-(2-{2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoicacid methyl ester (0.459 g).

Step D

To a solution of3-(2-{2-chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-vinyl)-benzoicacid methyl ester (0.459 g, 0.825 mmol) in methyl alcohol (20 mL) isadded 1 N sodium hydroxide solution (2.5 mL). The reaction is heated tomild reflux for 1 h and is cooled to room temperature. The reactionmixture is concentrated under reduced pressure. The residue is dissolvedin water and the aqueous solution is acidified with 5 N hydrochloricacid solution to form a white precipitate. The solid is filtered anddried overnight under reduced pressure to give the title compound (0.395g). ES/MS m/e 542.0 (M+1), 542.0 (M-H); HPLC purity: 95.56

Example 95

4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy-]-2-methyl-phenylethynyl}-benzoicAcid Step A

To a room temperature solution of5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole(50 mg, 0.110 mmol) in DMF (1 mL) are added 4-ethynyl-benzoic acidmethyl ester (18 mg, 0.110 mmol) and triethylamine (107 μL, 0.770 mmol).The reaction mixture is degassed for 20 minutes with nitrogen. To thereaction mixture are added dichloro(bistriphenylphosphine) palladium(II) (8 mg, 0.011 mmol, 10 mol %) and zinc (II) triflate (40 mg, 0.110mmol). The reaction mixture is heated to 80° C. After 3 h, the reactionis concentrated and the residue is chromatographed (40 g SiO₂, 0% to 5%EtOAc/Hexanes) to yield4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoicacid methyl ester (38 mg, 64%). LC/MS m/e 534.2 (M+1)

Step B

To an ambient temperature solution of4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoicacid methyl ester (32 mg, 0.0599 mmol) in dioxane (2 mL) is added asolution of lithium hydroxide (90 μL, 0.180 mmol, 2.0N in water). Thereaction mixture is stirred at room temperature overnight. The reactionis concentrated and the residue is partitioned between Et₂O and water.The aqueous layer pH is adjusted to approximately 4 and the aqueouslayer is extracted with a second portion of Et₂O. The combined organiclayers are washed with water, dried (MgSO₄), filtered, and concentratedto yield the title compound (32 mg, quant). LC-ES/MS m/e 520.2 (M+1),HPLC purity: 100%

Example 96

4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoicAcid Step A

To a solution of5-bromomethyl-1-(2,6-dichlorophenyl)-4-trifluoromethyl-1H-triazole(15.65 g, 41.7 mmol) and4-{[(4-hydroxy-2-methylphenyl)methylamino]methyl}-2-methyl benzoic acid,methyl ester (12.49 g, 41.7 mmol) in acetonitrile (120 mL) is addedpotassium carbonate (11.54 g, 83.4 mmol) at room temperature. Themixture is heated at 90° C. overnight. After 16 h, the reaction iscooled to room temperature and filtered through a pad of diatomaceousearth. The solvent is removed under reduced pressure. The residue isdiluted with MTBE and washed with 2N NaOH, water, and brine. The organiclayer is dried over magnesium sulfate, filtered, and evaporated toafford4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoicacid methyl ester (24.2 g, 97%). ES/MS m/e 593 (M+1)

Step B

To a solution of4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoicacid methyl ester (24.2 g, 40.7 mmol) in MeOH (150 mL) and THF (150 mL)is added 2N potassium hydroxide (102 mL, 203 mmol). The mixture isheated at 60° C. for 2 hours. The solvent is removed under reducedpressure. The residue is diluted with water, acidified to pH 3 with 2NHCl, and extracted with dichloromethane. The organic layer is dried overmagnesium sulfate, filtered, and evaporated under reduced pressure toafford the title compound as a white solid that is crystallized fromMeOH (20 g, 80%). ES/MS m/e 579 (M+1)

Example 976-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylicAcid

Step 16-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylicAcid Methyl Ester

Nitrogen is bubbled through a solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(0.2 g, 0.64 mmol) and6-(4-hydroxy-2-methyl-phenyl)-benzo[b]thiophene-3-carboxylic acid methylester (0.16 g, 0.53 mmol) in toluene (5 mL) for 10 minutes. Tri-n-butylphosphine (0.2 mL, 0.81 mmol) is added. Nitrogen is bubbled for anadditional 10 minutes followed by addition of1,1′-(azocarbonyl)-dipiperidine (202 mg, 0.801 mmol). The reaction isstirred at room temperature for 18 h. The crude reaction is concentratedonto silica and chromatographed (40 g SiO₂, 0% to 30% EtOAc/Hexanes) toyield the title compound (0.140 g, 44%). ES/MS m/e 592.0 (M+1)

Step 26-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylicAcid

To a solution of6-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-benzo[b]thiophene-3-carboxylicacid methyl ester (0.14 g, 0.23 mmol) in a 1:1:1 mixture of THF,methanol, water (3 mL) is added LiOH (0.10 g, 2.36 mmol). The reactionis stirred for 18 h at room temperature. The reaction is adjusted to pH3 with 1N HCl and extracted with EtOAc to yield the title compound (0.09g, 66%). LC-ES/MS m/e 576.0 (M−1)

Example 986-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid

Step 16-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy-]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid Methyl Ester

Nitrogen is bubbled through a solution of[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol(0.25 g, 0.80 mmol) and6-(4-hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indazole-3-carboxylic acidmethyl ester (0.2 g, 0.62 mmol) in toluene (10 mL) for 10 minutes.Tri-n-butyl phosphine (0.21 mL, 1.05 mmol) is added. Nitrogen is bubbledfor an additional 10 minutes followed by addition of1,1′-(azocarbonyl)-dipiperidine (0.27 g, 1.05 mmol). The reaction isstirred at room temperature for 18 hours. The crude reaction isconcentrated onto silica and chromatographed (40 g SiO₂, 0% to 50%EtOAc/Hexanes) to yield the title compound (0.28 g, 73%). LC-ES/MS m/e618.0 (M+1)

Step 26-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid

To a solution of6-{4-[3-(2,6-dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicacid methyl ester (0.13 g, 0.21 mmol) in a 1:1:1 mixture of THF,methanol, water (4.5 mL) is added LiOH (0.09 g, 2.10 mmol). The reactionis stirred for 18 h at room temperature. The reaction is adjusted to pH3 with 1N HCl and extracted with EtOAc to yield the title compound (0.12g, 92%). LC-ES/MS m/e 602.0 (M−1)

Example 996-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid

Step 16-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid Methyl Ester

Nitrogen is bubbled through a solution of[5-cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-yl]-methanol(0.23 g, 0.80 mmol) and6-(4-hydroxy-2-methyl-phenyl)-1-isopropyl-1H-indazole-3-carboxylic acidmethyl ester (0.2 g, 0.62 mmol) in toluene (10 mL) for 10 minutes.Tri-n-butyl phosphine (0.21 mL, 1.05 mmol) is added. Nitrogen is bubbledfor an additional 10 min followed by addition of1,1′-(azocarbonyl)-dipiperidine (0.27 g, 1.05 mmol). The reaction isstirred at room temperature for 18 h. The crude reaction is concentratedonto silica and chromatographed (40 g SiO₂, 0% to 40% EtOAc/Hexanes) toyield the title compound (0.11 g, 30%). LC-ES/MS m/e 590.0 (M+1)

Step 26-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicAcid

To a solution of6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicacid methyl ester (0.18 g, 0.30 mmol) in a 1:1:1 mixture of THF,methanol, water (6.0 mL) is added LiOH (0.13 g, 3.0 mmol). The reactionis stirred for 18 h at room temperature. The reaction is adjusted to pH3 with 1N HCl and extracted with EtOAc to yield the title compound (0.12g, 70%). LC-ES/MS m/e 576.0 (M+1).

1. A compound of

wherein p is 0, 1 or 2; X₁ is C or N and X₂ is C or N; provided thatboth X₁ and X₂ are not N; R¹ and R² are independently selected from thegroup consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃thiohaloalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, and halo; R³ isindependently selected from the group consisting of hydrogen, C₁-C₃alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, and halo; R^(4b)is selected from the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, C₃-C₆ cycloalkyl, and C₄-C₅ alkylcycloalkyl; R⁵ and R^(5a)are independently selected from the group consisting of hydrogen, andC₁-C₃ alkyl; R⁶ is selected from the group consisting of hydrogen, C₁-C₃alkyl, C₁-C₃ haloalkyl, halo, and —NO₂; L₁ is selected from the groupconsisting of a bond, CR^(a)═CR^(b), ethynyl, C₁-C₃ alkyl-S—, C₁-C₃alkyl-O—, N(R^(c))—C₁-C₃ alkyl, and —C₁-C₃ alkyl-N(R^(c))—, whereinR^(a) and R^(b) are independently selected from the group consisting ofhydrogen and C₁-C₃ alkyl; and R^(c)is independently selected from thegroup consisting of H, C₁-C₅ alkyl, C₁-C₃ alkylphenyl, and C₄-C₈alkylcycloalkyl; Ar¹ is selected from the group consisting of indolyl,benzothienyl, benzoisothiazolyl, indazolyl, naphthyl, phenyl, pyridinyl,pyrazolyl, pyrrolyl, thienyl, thiazolyl, and furanyl, each optionallysubstituted with one or two groups independently selected from the groupconsisting of hydroxy, C₁-C₃ alkyl, C₁-C₃ haloalkyl, halo, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, —OC₁-C₂ alkylphenyl, andNHC(O)R¹⁰; R⁷ is selected from the group consisting of —COOH, —C₁-C₃alkylCOOH, —O—C₁-C₃ alkylCOOH, —C₃-C₈ cycloalkylCOOH and, —CONR¹¹R¹¹;each R¹⁰ is independently selected from the group consisting ofhydrogen, C₁-C₃ alkyl, and phenyl; each R¹¹ is independently hydrogen,or C₁-C₅ alkyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 wherein p is 0 or 1; X₁ and X₂ are both C,or X₁ is N and X₂ is C; R¹ and R² are independently selected from thegroup consisting of hydrogen, fluoro, chloro, CF₃, SCF₃, OCF₃, R³ ishydrogen, fluoro, chloro C₁-C₃ alkyl, CF₃, SCF₃, or OCF₃; R^(4b) is H,C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, or C₃-C₄ cycloalkyl; R⁵and R^(5a) are each independently selected from H or C₁-C₃ alkyl; Ar¹group is phenyl, indolyl, pyridinyl, pyrrolyl, thienyl, naphthyl,thiazolyl, furanyl, pyrazolyl, indazolyl, benzoisothiazolyl, andbenzothienyl each optionally substituted with one to two groupsindependently selected from C₁-C₅ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkoxy,and C₁-C₃ haloalkyl; R⁶ is hydrogen, methyl, ethyl or chloro; L₁ is abond, ethenyl, —CH(CH₃)—S—, C(CH₃)₂—S—, —CH₂O—, —CH₂CH₂O—, —CH(CH₃)—O—,—CH(CH₃)CH₂—O—, —CH(CH₂CH₃)—O—, —CH₂NH—, —CH₂CH₂NH—, —N(R^(c))CH₂—,N(R^(c))CH₂CH₂—, or N(R^(c))CH₂CH₂CH₂—; wherein R^(c) is hydrogen, C₁-C₂alkyl, benzyl or —CH₂CH₂—O—CH₂—; R⁷ is COOH, —CH₂COOH, —CH(CH₃)COOH,-cyclopropylCOOH, —C(CH₃)₂COOH, CONH₂, C(O)NHCH₃, or C(O)NHCH₂CH₃; R¹⁰is hydrogen or C₁-C₂ alkyl; and R¹¹ is hydrogen or C₁-C₂ alkyl.
 3. Acompound according to claim 1, wherein X₁ and X₂ are both C; p is 1; R¹and R² are independently selected from the group consisting of chloro,fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R³is hydrogen; R^(4b) is trifluoromethyl, isopropyl or cyclopropyl; L₁ isethenyl, acetylene, —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ and R^(5a) areboth hydrogen; R⁶ is hydrogen, methyl, chloro or bromo; Ar¹ is phenyl,indolyl, indazolyl, benzothienyl, or benzoisothiazolyl, each optionallysubstituted with a group independently selected from methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.
 4. A compound according to claim 1,wherein X₁ and X₂ are both C; p is 1; R¹ and R² are independentlyselected from the group consisting of chloro, fluoro, trifluoromethyl,thiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is —N(CH₃)CH₂—, or—N(CH₃)CH₂CH₂—; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl,ethyl or chloro; Ar¹ is phenyl, benzoisothiazolyl, indazolyl, indolyl orbenzothienyl, each optionally substituted with a group independentlyselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,ethoxy, isopropoxy and cyclopropoxy; and R⁷ is COOH.
 5. A compoundaccording to claim 1, wherein X₁ and X₂ are both C; p is 1; R¹ and R²are independently selected from the group consisting of hydrogen,chloro, fluoro, trifluoromethyl thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ and R^(5a) areboth hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹ is phenyl,optionally substituted with a group selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy;and R⁷ is COOH.
 6. A compound according to claim 1, wherein X₁ and X₂are both C; p is 1; R¹ and R² are independently selected from the groupconsisting of hydrogen, chloro, fluoro, trifluoromethylthiotrifluoromethyl, and trifluoromethoxy; R³ is hydrogen; R^(4b) istrifluoromethyl, isopropyl or cyclopropyl; L₁ is a bond, —N(CH₃)CH₂—, or—N(CH₃)CH₂CH₂—; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl,ethyl or chloro; Ar¹ is phenyl, benzoisothiazolyl, indazolyl, indolyl orbenzothienyl, each optionally substituted with a group independentlyselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,ethoxy, isopropoxy and cyclopropoxy; and R⁷ is COOH.
 7. A compoundaccording to claim 1, wherein X₁ and X₂ are both C; p is 1; R¹ and R²are independently selected from the group consisting of hydrogen,chloro, fluoro, trifluoromethyl thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ and R^(5a) areboth hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹ isbenzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionallysubstituted with a group independently selected from methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.
 8. A compound according to claim 1,wherein X₁ and X₂ are both C; p is 1; R¹ and R² are independentlyselected from the group consisting of hydrogen, chloro, fluoro,trifluoromethyl thiotrifluoromethyl, and trifluoromethoxy; R³ ishydrogen; R^(4b) is trifluoromethyl, isopropyl or cyclopropyl; L₁ is abond; R⁵ and R^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl orchloro; Ar¹ is phenyl, benzoisothiazolyl, indazolyl, indolyl orbenzothienyl, each optionally substituted with a group independentlyselected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy,ethoxy, isopropoxy and cyclopropoxy; and R⁷ is COOH.
 9. A compoundaccording to claim 1, wherein X₁ and X₂ are both C; p is 1; R¹ and R²are independently selected from the group consisting of hydrogen,chloro, fluoro, trifluoromethyl thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R⁴ is trifluoromethyl, isopropyl orcyclopropyl; L₁ is a bond; R⁵ and R^(5a) are both hydrogen; R⁶ ishydrogen, methyl, ethyl or chloro; Ar¹ is phenyl optionally substitutedwith a group selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.
 10. A compound according to claim 1, wherein X₁ and X₂ are both C;p is 1; R¹ and R² are independently selected from the group consistingof chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R⁴ is trifluoromethyl, isopropyl orcyclopropyl; L₁ is ethenyl; R⁵ and R^(5a) are both hydrogen; R⁶ ishydrogen, methyl, ethyl or chloro; Ar¹ is phenyl, thienyl, pyrrolyl,furanyl, or thiazolyl, each optionally substituted with a groupindependently selected from methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R⁷ isCOOH.
 11. A compound according to claim 1, wherein X₁ and X₂ are both C;p is 1; R¹ and R² are independently selected from the group consistingof chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, andtrifluoromethoxy; R³ is hydrogen; R^(4b) is trifluoromethyl, isopropylor cyclopropyl; L₁ is ethenyl, —N(CH₃)CH₂—, or —N(CH₃)CH₂CH₂—; R⁵ andR^(5a) are both hydrogen; R⁶ is hydrogen, methyl, ethyl or chloro; Ar¹is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionallysubstituted with a group independently selected from methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy andcyclopropoxy; and R⁷ is COOH.
 12. A compound selected from the groupconsisting of:4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoicacid,3-[({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoicacid,3-[({4-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoicacid,4-[({4-[5-Isopropyl-3-(2,6-Dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoicacid,4-[({4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methyl-benzoicacid,3-[({4-[3-(2-Chloro-6-fluoro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-benzoicacid,4-[({6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoicacid, or a pharmaceutically acceptable salt thereof.
 13. The compound4-[({4-[3-(2,6-dichlorophenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methylphenyl}-methylamino)-methyl]-2-methyl-benzoicacid.
 14. The compound6-{4-[3-(2,6-Dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicacid.
 15. The compound6-{4-[5-Cyclopropyl-3-(2,6-dichloro-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylicacid.
 16. A method of treating dyslipidemia comprising administering atherapeutically effective amount of a compound according to claim 1 to apatient in need thereof.
 17. (canceled)
 18. (canceled)
 19. (canceled)20. A method of treating atherosclerosis comprising administering atherapeutically effective amount of a compound according to claim 1 to apatient in need thereof.
 21. A method of treating diabetes and/orcomplications thereof comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a patient in needthereof.
 22. A pharmaceutical composition comprising a compoundaccording to claim 1 and a carrier, diluent, or excipient. 23.(canceled)